Modified release tablet of bupropion hydrochloride

ABSTRACT

A modified-release tablet of bupropion hydrochloride comprising (i) a core comprising an effective amount of bupropion hydrochloride, a binder, a lubricant; and (ii) a control releasing coat surrounding said core; and (iii) a moisture barrier surrounding said control releasing coat, wherein the modified-release tablet is bioequivalent to Wellbutrin® or Zyban®/Wellbutrin®SR tablets.

FIELD OF THE INVENTION

The present invention relates to a modified-release tablet ofpharmaceutically acceptable salts of bupropion, preferably bupropionhydrochloride.

BACKGROUND

Bupropion is an antidepressant chemically unrelated to tricyclics,tetracyclics, selective serotonin re-uptake inhibitors (SSRIs), or otherknown antidepressant agents. The drug resembles a psycho stimulant interms of its neurochemical and behavioral profiles in vivo, but it doesnot reliably produce stimulant-like effects in humans at clinicallyprescribed doses. Its structure closely resembles that of diethylpropionand it is related to phenylethylamines. It is designated as(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanonehydrochloride and by its generic name amfebutamone hydrochloride.Bupropion hydrochloride is commercially available as an immediaterelease form (Wellbutrin®) and a sustained release form (Wellbutrin® SRand Zyban®). Both Wellbutrin® SR and Zyban® are chemically andpharmaceutically identical.

The neurochemical mechanism of the antidepressant effect of bupropion isnot well known. Bupropion does not inhibit monoamine oxidase. Bupropionaffects chemicals within the brain that nerves use to send messages toeach other. These chemical messengers are called neurotransmitters. Theneurotransmitters that are released by nerves are taken up again by thenerves that release them for reuse (This is referred to as reuptake).Many experts believe that depression is caused by an imbalance among theamounts of neurotransmitters that are released. It is believed thatbupropion works by inhibiting the reuptake of the neurotransmittersdopamine, serotonin, and norepinephrine, an action which results in moredopamine, serotonin, and norepinephrine made available to transmitmessages to other nerves. Accordingly, bupropion is unique in that itsmajor effect is on dopamine, an effect, which is not shared by the SSRIs(e.g. paroxetine (Paxil®), fluoxetine (Prozac®), sertraline (Zoloft®))or the tricyclic antidepressants or TCAs (e.g. amitriptyline (Elavil®),imipramine (Tofranil®), desipramine (Norpramin®)).

Wellbutrin® and Wellbutrin® SR are used for the management ofdepression. Zyban® has been approved as an aid to patients wanting toquit smoking. Wellbutrin®, the immediate release formulation ofbupropion, is dosed three times a day, preferably with 6 or more hoursin between doses. For patients requiring more that 300 mg bupropion aday, each dose should not exceed 150 mg. This requires administration ofthe tablets at least 4 times a day with at least 4 hours in betweendoses. The immediate release formulation results in more than a 75%release of the bupropion into the dissolution media in about 45 minutes,and one of the major side effects of bupropion has been the incidence ofseizures, which in part appears to be strongly associated with theimmediate release of the bupropion into the system. Accordingly,sustained release products were developed to avoid the incidence ofseizures. The sustained release products are dosed twice daily.

In general, patient compliance is a problem with medications thatrequire a multiple dosing regimen and is especially problematic withdepressed individuals. While sustained release formulations havesimplified the dosing regimen and increased patient compliance, there isstill room for further simplifying the dosing regimen and furtherimproving patient adherence to the dosing regimen. The development of anapproved stable once daily modified-release bupropion formulation wouldbe an advance in the art.

Sustained release tablet forms of bupropion have been described in theprior art. U.S. Pat. No. 4,687,660 discloses a tablet formed of a coreand a coating, where the core comprises bupropion hydrochloride togetherwith excipient(s) and optionally an osmotic enhancing agent and wherethe coating comprises a water-insoluble, water-permeable film-formingpolymer (such as cellulose acetate), a pore-forming agent (such asimpalpable lactose and sodium carbonate), and optionally a so-calledwater-permeability enhancing agent (such as polyethylene glycol) andagain optionally a plasticizer.

U.S. Pat. Nos. 5,358,970 and 5,427,798 describe a sustained releaseformulation of bupropion hydrochloride based on matrix technology. Theterm matrix refers to a tablet where the drug is embedded in anexcipient that makes a non-disintegrating core called a matrix. Drugdiffusion occurs through this core. As bupropion hydrochloride isunstable, the product described in the above two patents requires astabilizer to achieve sufficient stability. This stabilizer is an acidiccompound, preferably cysteine hydrochloride. The major disadvantage ofmatrix systems is that they generally display a first order releaseprofile. That is, initially drug particles located at the surface of thetablet will be dissolved and drug released rapidly. Thereafter, drugparticles at successively increasing distances from the surface of thetablet will be dissolved and released by diffusion in the pores to theexterior of the tablet. Thus, the diffusion distance of the drug willincrease as the release process proceeds. It is normally preferred thata zero order or near zero order release profile is obtained rather thana first order release profile. Zero order release system provides aconstant rate of drug release over a defined period of time. It is usedprimarily for drugs with short half-lives so that constant blood levelsof the active drug compounds can be maintained with fewer doses.

U.S. Pat. No. 6,589,553 and International Publication No. WO 02/062299purportedly describes a once daily capsule formulation with twopopulations of coated pellets, each of which release bupropionhydrochloride at a different pH. One population of pellets is coated torelease the drug at a pH corresponding to about 4.8 and lower. Therelease of the drug from this population of pellets is expected to occurin the upper GI tract. The other population of pellets is coated torelease the drug at a pH of 7 and above. The release of bupropion fromthis population is expected to occur in the lower GI tract. In oneexample shown, the relative bioavailability of bupropion to Zyban® wasonly 40% in terms of C_(max) ratio and only 80% in terms of AUC_(0-inf)ratio. In another example shown, the relative bioavailability ofbupropion to Zyban® was only 48% and 59% in terms of C_(max) andAUC_(0-inf). The references further describe the introduction of a thirdpopulation of uncoated active pellets, which purportedly result in afurther modification and improvement of the bupropion release. Based onthe mean plasma concentration-time profile shown in FIGS. 3 and 4 ofthese references it is not readily apparent that the introduction of theuncoated active pellets would result in a once daily bioequivalentformulation (reference product is Zyban®). Also, neither one of the tworeferences present any drug stability data.

U.S. Pat. No. 6,033,686 describes a controlled release tablet, free ofstabilizer and free of pore forming agent comprising a core consistingessentially of bupropion hydrochloride, a binder and a lubricant; and acoating comprising a water-insoluble, water-permeable film formingpolymer, a plasticizer and a water-soluble polymer. The productresulting from the '686 patent is a twice daily product.

U.S. Pat. Nos. 6,096,341 and 6,143,327 both relate to a delayed releaseformulation of bupropion hydrochloride. The '341 patent provides for acontrolled release tablet, free of stabilizer and free of pore formingagent comprising a core consisting essentially of bupropionhydrochloride, a binder and a lubricant; and a coating consistingessentially of a water-insoluble, water-permeable film forming polymer,a plasticizer and a water-soluble polymer. The '327 patent provides fora controlled release tablet, free of stabilizer and free of pore formingagent comprising a core consisting essentially of bupropionhydrochloride, a binder and a lubricant; and a control-releasing coatconsisting essentially of a water-insoluble, water-permeable filmforming polymer, a plasticizer and a water-soluble polymer and a secondcoat consisting essentially of a methacrylic polymer and a plasticizer.The formulation as described in the '327 patent does not however,conform to the FDA's guidelines for bioequivalency (see Example 8herein).

There is currently no approved commercially available stable once dailybupropion dosage form. Accordingly, there is a need for a stable oncedaily bioequivalent formulation of bupropion or a pharmaceuticallyacceptable salt thereof.

Definitions

“Modified release dosage forms” are defined by the USP as those whosedrug release characteristics of time course and/or location are chosento accomplish therapeutic or convenience objectives not offered byconventional forms. An extended-release dosage form allows a twofoldreduction in dosing frequency or increase in patient compliance ortherapeutic performance. The USP considers that the terms controlledrelease, prolonged release and sustained release are interchangeablewith extended release. Accordingly, the terms “modified-release”,controlled-release”, “prolonged-release”, “extended-release”, and“sustained-release” are used interchangeably herein.

The term “pharmaceutically acceptable salt of bupropion” includes saltsthat are physiologically tolerated by a patient. Such salts aretypically prepared from inorganic acids or bases and/or organic acids orbases. Examples of such acids and bases are well known to those ofordinary skill in the art. The invention in particular contemplates theuse of bupropion hydrochloride, although the use of otherpharmaceutically acceptable salts is within the scope of the invention.The term “effective amount” as used herein means a “pharmaceuticallyeffective amount”. A “pharmaceutically effective amount” is the amountor quantity of the pharmaceutically acceptable salt of bupropion, whichis sufficient to elicit an appreciable biological response whenadministered to a patient. It will be appreciated that the precisetherapeutic dose will depend on the age and condition of the patient andthe nature of the condition to be treated and will be at the ultimatediscretion of the attendant physician.

The term “moisture barrier” as used herein is one, which impedes orretards the absorption of moisture. It is known that bupropionhydrochloride is highly hygroscopic and, as such, is relatively unstableand susceptible to decomposition over time especially under highhumidity conditions. The proportion of the components of the moisturebarrier and the amount of the moisture barrier applied onto thecontrol-releasing coat is such that the moisture barrier does not fallwithin the USP definition and requirement for and enteric coat.Preferably, the moisture barrier is comprised of an enteric and/oracrylic polymer, preferably an acrylic polymer, optionally aplasticizer, and a permeation enhancer. The permeation enhancer is ahydrophilic substance, which allows water to enter without physicaldisruption of the coating. The moisture barrier may additionally containother conventional inert excipients, which may improve processing of themodified-release formulation described herein.

As used herein “total impurities” mean all degradation productsresulting from the degradation of bupropion hydrochloride. The“degradation products” include those listed on page 281 of the 26^(th)edition of the USP and any other degradation products that may appear aspeaks on a chromatogram during the assay.

The modified-release tablets of the invention comprising arebioequivalent to Wellbutrin® or Zyban®/Wellbutrin®SR tablets. The term“bioequivalent” means the absence of a significant difference in therate and extent to which the active ingredient or active moiety inpharmaceutical equivalents or pharmaceutical alternatives becomesavailable at the site of drug action when administered at the same molardose under similar conditions in an appropriately designed study. Wherethere is an intentional difference in rate (e.g., in certain extendedrelease dosage forms), certain pharmaceutical equivalents oralternatives may be considered bioequivalent if there is no significantdifference in the extent to which the active ingredient or moiety fromeach product becomes available at the site of drug action. This appliesonly if the difference in the rate at which the active ingredient ormoiety becomes available at the site of drug action is intentional andis reflected in the proposed labeling, is not essential to theattainment of effective body drug concentrations on chronic use, and isconsidered medically insignificant for the drug.

SUMMARY OF THE INVENTION

The present invention relates to a modified-release tablet of apharmaceutically acceptable salt of bupropion, preferably bupropionhydrochloride. The advantage of the modified-release tablets of theinvention not afforded by the prior art commercially availableWellbutrin® or Zyban®/Wellbutrin® SR tablets is that themodified-release tablets allow for a once daily administration regimen,is bioequivalent to the commercially available prior art tablets and donot exhibit a food effect.

In accordance with one aspect of the present invention, there isprovided a modified-release tablet, comprising (i) a core comprising aneffective amount of a pharmaceutically acceptable salt of bupropion, abinder, a lubricant; and (ii) a control-releasing coat surrounding saidcore; and (iii) a moisture barrier surrounding said control-releasingcoat; and; wherein the modified-release tablet is bioequivalent andexhibits a dissolution profile such that after about 2 hours, no morethan about 20%, preferably about 2% to about 18%, more preferably about4% to about 8%, and most preferably about 5% of the bupropionhydrochloride content is released, after about 4 hours, about 15% toabout 45%, preferably about 21% to about 37%, more preferably about 28%to about 34%, and most preferably about 32% of the bupropionhydrochloride content is released, after about 8 hours, about 40% toabout 90%, preferably about 60% to about 85%, more preferably about 68%to about 74%, and most preferably about 74% of the bupropionhydrochloride content is released and after about 16 hours no less thanabout 80%, preferably no less than about 93%, more preferably no lessthan about 96%, and most preferably no less than about 99% of thebupropion hydrochloride content is released.

In one embodiment the moisture barrier does not function as an entericcoat as defined by a USP test, which requires for an enteric layercoated tablet, when placed in 0.1N HCl for one hour, that the totalamount of drug released does not exceed 10% and not less than 75% of thedrug is released at 45 minutes in pH 6.8 buffer.

In one embodiment of the present invention, the pharmaceuticallyacceptable salt of bupropion is present at least at about 94% by weightof the dry core weight. Preferably, the modified-release tablet of thepresent invention contains from about 50 mg to about 450 mg of bupropionhydrochloride. Most preferably, the tablets of the invention containabout 150 mg or 300 mg bupropion hydrochloride.

In another embodiment of the present invention, the amount of binder ispresent preferably from about 1% to about 6% and more preferably atabout 3% by weight of the dry core weight. The binder is preferablypolyvinyl alcohol.

In another embodiment of the present invention, the lubricant is presentpreferably from about 1% to about 6% and more preferably at about 3% byweight of the dry core weight. The lubricants useful for the tablets ofthe present invention may be selected from the group consisting ofglyceryl behenate, stearic acid, hydrogenated vegetable oils and anycombination thereof. The preferred lubricant is glyceryl behenate.

In another embodiment of the present invention, the control-releasingcoat consists essentially of a water-insoluble water-permeablefilm-forming polymer and the amount present may vary from about 35% toabout 60% by weight of the control-releasing coat dry weight.Preferably, the amount of water-insoluble water-permeable film-formingpolymer is present at about 50% by weight of the control-releasing coatdry weight for the 150 mg dose and at about 45% by weight of thecontrol-releasing coat dry weight for the 300 mg dose. Thewater-insoluble water-permeable film forming polymers may be selectedfrom the group consisting of cellulose ethers, cellulose esters,polyvinyl alcohol and any combination thereof. The preferredwater-insoluble water-permeable film forming polymers are the ethylcelluloses and may be selected from the group consisting of ethylcellulose grade PR 100, ethyl cellulose grade PR 20 and any combinationthereof. The preferred water-insoluble water-permeable film-formingpolymer is ethyl cellulose grade PR 100.

In another embodiment of the present invention, the amount ofplasticizer is present from about 6% to about 30% and more preferably atabout 12% by weight of the control-releasing coat dry weight. Theplasticizers useful for the tablets of the present invention may beselected from the group consisting of polyols, organic esters,oils/glycerides and any combination thereof. The preferred plasticizeris polyethylene glycol 1450.

In another embodiment of the present invention, the amount ofwater-soluble polymer present may vary from about 25% to about 50% byweight of the control-releasing coat dry weight. Preferably, thewater-soluble polymer is present at about 43% by weight of thecontrol-releasing coat. The water-soluble polymer may be selected fromthe group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose and any combination thereof.The preferred water-soluble polymer is polyvinylpyrrolidone.

In another embodiment of the present invention, the ratio of thewater-insoluble water-permeable film-formingpolymer:plasticizer:water-soluble polymer for the 150 mgmodified-release bupropion hydrochloride tablet of the invention mayvary from about 3:1:4 to about 5:1:3 with the preferred ratio being4:1:3.

In another embodiment of the present invention, the ratio of thewater-insoluble water-permeable film-formingpolymer:plasticizer:water-soluble polymer for the 300 mgmodified-release bupropion hydrochloride tablet of the invention mayvary from about 7:2:6 to about 19:5:18 with the preferred ratio being13:4:12.

In another embodiment of the present invention, the weight gained aftercoating the tablet core with the control-releasing coat may vary from 3%to about 30% off the weight of the dry tablet core. For the 150 mg doseof the modified-release tablet of the present invention, the weightgained may vary from about 13% to about 16% of the dry tablet coreweight with the preferred weigh gain being about 15% of the weight ofthe dry tablet core. For the 300 mg dose modified-release tablet of theinvention, the weight gained after application of the control-releasingcoat may vary from about 8% to about 10% of the dry tablet core weightwith a 9% weight gain being preferred.

In another embodiment off the present invention, the moisture barriercomprises an enteric and/or acrylic polymer, a plasticizer and apermeation enhancer and is present in a ratio of about 13:2:5. Theenteric and/or acrylic polymer is preferably an acrylic polymer, whichin turn is preferably a methacrylic acid copolymer availablecommercially as Eudragit® L 30 D-55. Although the amount of methacrylicacid copolymer present may vary from about 30% to about 90% by weight ofthe moisture barrier dry weight, it is preferable that the amount of themethacrylic acid copolymer is present at about 66% of the moisturebarrier dry weight.

In another embodiment of the present invention, the plasticizer may beselected from the group consisting of polyols, organic esters,oils/glycerides and any combination thereof. The preferred plasticizerfor use in the moisture barrier is a combination of a polyol and organicester. The preferred polyol in the combination is polyethylene glycol1450 with triethyl citrate being the preferred organic ester. The ratioof the organic ester to the polyol is preferably 1:2. It is preferablethat the plasticizer be present from about 1% to about 30% and morepreferably at about 10% by weight of the moisture barrier dry weight.

In another embodiment of the present invention, the permeation enhanceris a hydrophilic substance and may be selected from the group consistingof silicon dioxide, colloidal silicon, lactose, hydrophilic polymers,sodium chloride, aluminum oxide, colloidal aluminum oxide, silica,microcrystalline cellulose and any combination thereof. The permeationenhancer is preferably silicon dioxide and is present from about 20% toabout 40% and more preferably at about 25% by weight of the moisturebarrier dry weight.

In another embodiment of the present invention, the moisture barrier isapplied such that the weight gained after application of the moisturebarrier is no more than about 6% and preferably no more than about 2.5%of the tablet dry weight for both the 150 mg and 300 mg dosemodified-release tablets of the invention.

In another embodiment of the present invention, the modified-releasetablet of the invention provides for a stable bupropion hydrochlorideformulation such that at least about 95% and preferably at least about97.5% and even 98.5% or even 99% of the bupropion hydrochloride remainsstable after about 12 months storage at 25° C.±2° C./60% RH±5% RH.

In another embodiment of the present invention, the modified-releasetablet of the invention provides for a stable bupropion hydrochlorideformulation such that at least about 95% and preferably at least about97.5% and even 98.5% or even 99% of the bupropion hydrochloride remainsstable after about 18 months storage at 25° C.±2° C./60% RH±5% RH

In another embodiment of the present invention, the modified-releasebupropion hydrochloride tablets of the invention are bioequivalent toeither Wellbutrin® or Zyban®/Wellbutrin® SR tablets and do not exhibit afood effect.

In another aspect of the invention, the moisture barrier substantiallyimpedes or retards the absorption of moisture into the tablet, therebyincreasing the stability of the bupropion hydrochloride

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be further understood from the followingdetailed description with reference to the following drawings in which:

FIG. 1A is a graph illustrating the dissolution profile of a 150 mgdosage strength bupropion hydrochloride modified-release tablets withthree different release rates according to an embodiment of theinvention.

FIG. 1B is a graph illustrating the dissolution profile of a 300 mgdosage strength bupropion hydrochloride modified-release tablets withthree different release rates according to an embodiment of theinvention.

FIG. 2A is a graph illustrating the statistical analysis for RelativeResponse Factors (RRF) corrected total impurities content in the 150 mgdosage strength bupropion hydrochloride modified-release tabletsaccording to an embodiment of the invention stored at 25° C.±2° C./60%RH±5% RH in HDPE bottles (7 ct, 40 cc and 30 ct, 100 cc).

FIG. 2B is a graph illustrating the statistical analysis for RelativeResponse Factors (RRF) corrected total impurities content in the 300 mgdosage strength bupropion hydrochloride modified-release tabletsaccording to an embodiment of the invention stored at 25° C.±2° C./60%RH±5% RH in HDPE bottles (7 ct, 40 cc and 30 ct, 100 cc).

FIG. 3A is a graph illustrating the mean plasma bupropion concentrationsof a dosage strength equivalency study after administration of 2×150 mg(q.d.) and 1×300 mg (q.d.) dosage strength modified-release bupropionhydrochloride tablets according to an embodiment of the invention.

FIG. 3B is a graph illustrating the mean plasma hydroxybupropionconcentrations of a dosage strength equivalency study afteradministration of 2×150 mg (q.d.) and 1×300 mg (q.d.) dosage strengthmodified-release bupropion hydrochloride tablets according to anembodiment of the invention.

FIG. 3C is a graph illustrating the mean plasma bupropion threoaminoalcohol concentrations of a dosage strength equivalency study afteradministration of 2×150 mg (q.d.) and 1×300 mg (q.d.) dosage strengthmodified-release bupropion hydrochloride tablets according to anembodiment of the invention.

FIG. 3D is a graph illustrating the mean plasma bupropion erythroaminoalcohol concentrations of a dosage strength equivalency study afteradministration of 2×150 mg (q.d.) and 1×300 mg (q.d.) dosage strengthmodified-release bupropion hydrochloride tablets according to anembodiment of the invention.

FIG. 4A is a graph illustrating the effect of food on the mean plasmabupropion concentrations after a single dose administration of a 150 mgdosage strength modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention.

FIG. 4B is a graph comparing the mean plasma bupropion concentrationsshown in FIG. 4A with the mean plasma bupropion concentrations after asingle dose administration of the prior art 150 mg Zyban® tablet.

FIG. 4C is a graph comparing the mean plasma hydroxybupropionconcentrations after a single dose administration of a 150 mg dosagestrength modified-release bupropion hydrochloride tablet according to anembodiment of the invention with the mean plasma hydroxybupropionconcentrations after a single dose administration of the prior art 150mg Zyban® tablet.

FIG. 4D is a graph comparing the mean plasma bupropion threoaminoalcohol concentrations after a single dose administration of a 150 mgdosage strength modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention with the mean plasmahydroxybupropion concentrations after a single dose administration ofthe prior art 150 mg Zyban® tablet.

FIG. 4E is a graph comparing the mean plasma bupropion erythroaminoalcohol concentrations after a single dose administration of a 150 mgdosage strength modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention with the mean plasmahydroxybupropion concentrations after a single dose administration ofthe prior art 150 mg Zyban® tablet.

FIG. 5A is a graph comparing the effect of food on the mean plasmabupropion concentrations of a single dose once-daily 300 mg dosagestrength modified-release bupropion hydrochloride tablet according to anembodiment of the invention.

FIG. 5B is a graph comparing the effect of food on the mean plasmahydroxybupropion concentrations of a single dose once-daily 300 mgdosage strength modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention.

FIG. 5C is a graph comparing the effect of food on the mean plasmabupropion threoamino alcohol concentrations of a single dose once-daily300 mg dosage strength modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention.

FIG. 5D is a graph comparing the effect of food on the mean plasmabupropion threoamino alcohol concentrations of a single dose once-daily300 mg dosage strength modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention.

FIG. 6A is a graph illustrating the mean steady state blood plasmabupropion concentrations after multiple dosing of a once daily 300 mgmodified-release bupropion hydrochloride tablet according to anembodiment of the invention when administered to a patient in the fastedstate.

FIG. 6B is a graph comparing the mean steady state blood plasmabupropion concentrations shown in FIG. 5A with the mean steady stateplasma bupropion concentrations after multiple dosing of the prior artWellbutrin® tablet in the fasted state.

FIG. 6C is a graph comparing the mean steady state blood plasmahydroxybupropion concentrations after multiple dosing of a once daily300 mg modified-release bupropion hydrochloride tablet according to anembodiment of the invention when administered to a patient in the fastedstate with the mean steady state plasma hydroxybupropion concentrationsafter multiple dosing of the prior art Wellbutrin® tablet in the fastedstate.

FIG. 6D is a graph comparing the mean steady state blood plasmabupropion threoamino alcohol concentrations after multiple dosing of aonce daily 300 mg modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention when administered to apatient in the fasted state with the mean steady state plasma bupropionthreoamino alcohol concentrations after multiple dosing of the prior artWellbutrin® tablet in the fasted state.

FIG. 6E is a graph comparing the mean steady state blood plasmabupropion erythroamino alcohol concentrations after multiple dosing of aonce daily 300 mg modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention when administered to apatient in the fasted state with the mean steady state plasma bupropionerythroamino alcohol concentrations after multiple dosing of the priorart Wellbutrin® tablet in the fasted state.

FIG. 7A is a graph illustrating the mean steady state blood plasmabupropion concentrations after multiple dosing of a once daily 300 mgmodified-release bupropion hydrochloride tablet according to anembodiment of the invention under fasted conditions.

FIG. 7B is a graph comparing the mean steady state blood plasmabupropion concentrations shown in FIG. 7A with the mean steady stateblood plasma bupropion concentrations after multiple dosing of the priorart 150 mg (b.i.d.) Zyban® tablets under fasted conditions.

FIG. 7C is a graph comparing the mean steady state blood plasmahydroxybupropion concentrations after multiple dosing of a once daily300 mg modified-release bupropion hydrochloride tablet according to anembodiment of the invention under fasted conditions with the mean steadystate blood plasma hydroxybupropion concentrations after multiple dosingof the prior art 150 mg (b.i.d.) Zyban® tablets under fasted conditions.

FIG. 7D is a graph comparing the mean steady state blood plasmabupropion threoamino alcohol concentrations after multiple dosing of aonce daily 300 mg modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention under fasted conditions withthe mean steady state blood plasma bupropion threoamino alcoholconcentrations after multiple dosing of the prior art 150 mg (b.i.d.)Zyban® tablets under fasted conditions.

FIG. 7E is a graph comparing the mean steady state blood plasmabupropion erythroamino alcohol concentrations after multiple dosing of aonce daily 300 mg modified-release bupropion hydrochloride tabletaccording to an embodiment of the invention under fasted conditions withthe mean steady state blood plasma bupropion erythroamino alcoholconcentrations after multiple dosing of the prior art 150 mg (b.i.d.)Zyban® tablets under fasted conditions.

DETAILED DESCRIPTION OF THE INVENTION

The invention described herein relates to a modified-release tablethaving a core comprising a pharmaceutically acceptable salt of bupropionand conventional excipients, surrounded by a control-releasing coat,which controls the release of the pharmaceutically acceptable salt ofbupropion, and a moisture barrier, which surrounds the control-releasingcoat. The modified-release tablet of the invention is bioequivalent.

1. The Core

The core of the modified-release tablet comprises an effective amount ofa pharmaceutically acceptable slat of bupropion, a binder, and alubricant and may contain other conventional inert excipients. Theamount of the active drug present may vary in an amount from about 50%to about 90% by weight of the tablet dry weight, and preferably fromabout 70% to about 90% by weight of the tablet dry weight. Thepharmaceutically acceptable salt of bupropion is preferably bupropionhydrochloride. The tablet comprises an amount of bupropion hydrochloridethat can vary from about 50 mg to about 450 mg. Preferably, the tabletcomprises 150 mg or 300 mg of bupropion hydrochloride. For a 150 mg dosetablet the bupropion hydrochloride is about 78% by weight of the tabletdry weight. For the 300 mg dose, the amount of bupropion hydrochlorideis present at about 83% by weight of the tablet dry weight. For both the150 mg and 300 mg dose bupropion hydrochloride modified-release tabletsof the invention, the amount of bupropion hydrochloride is present atabout 94% by weight of the dry core for each dose.

A binder (also sometimes called adhesive) is added to a drug-fillermixture to ensure that granules and tablets can be formed with therequired mechanical strength. Binders can be added to the formulation indifferent ways: (1) as a dry powder, which is mixed with otheringredients before wet agglomeration, (2) as a solution, which is usedas agglomeration liquid during wet agglomeration, and is referred to asa solution binder, and (3) as a dry powder, which is mixed with theother ingredients before compaction. In this form the binder is referredto as a dry binder. Solution binders are generally considered the mosteffective, and this is therefore the most common way of incorporating abinder into granules. The binder used herein is in the form of asolution binder. Non-limiting examples of binders useful for the coreinclude water-soluble polymers such as modified starch, gelatin,polyvinylpyrrolidone, cellulose derivatives (such as for examplehydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC))and polyvinyl alcohol. The amount of binder present may vary from about0.5% to about 15% by weight of the tablet dry weight, preferably fromabout 1% to about 6% by weight of the tablet dry weight, and mostpreferably about 3% by weight of the tablet dry weight. For both the 150mg and 300 mg dose tablets, the amount of binder may be presentpreferably from about 1% to about 6% by weight of each dry core weightand more preferably at about 3% by weight of each dry core weight. Thepreferred binder is polyvinyl alcohol.

Lubricants are added to pharmaceutical formulations to ensure thattablet formation and ejection can occur with low friction between thesolid and the die wall. High friction during tabletting can cause aseries of problems, including inadequate tablet quality (capping or evenfragmentation of tablets during ejection, and vertical scratches ontablet edges) and may even stop production. Accordingly, lubricants areadded to almost all tablet formulations including the bupropionhydrochloride tablet formulation described herein. Non-limiting examplesof lubricants useful for the core include glyceryl behenate, stearicacid, hydrogenated vegetable oils (such as hydrogenated cottonseed oil(Sterotex®), hydrogenated soybean oil (Sterotex® (HM) and hydrogenatedsoybean oil & castor wax (Sterotex® K), stearyl alcohol, leucine andpolyethylene glycol (MW 4000 and higher). The lubricant is preferablyglyceryl behenate. The amount lubricant present may vary from about 1%to about 5% by weight of the tablet dry weight, preferably from about 2%to about 3% by weight of the tablet dry weight, and most preferablyabout 2.5% by weight of the tablet dry weight. For the 150 mg and 300 mgdose modified-release tablets of the invention the lubricant is presentat about 2.5% by weight of the tablet dry weight and preferably fromabout 1% to about 6% by weight of the dry core weight and morepreferably at about 3% by weight of the dry core weight for bothdosages.

At this stage, the core formulation is an immediate release formulationresulting in 100% dissolution of the bupropion hydrochloride within 1hour (data not shown). Ideally the core comprises only an effectivepharmaceutical amount of pharmaceutically acceptable salt of bupropion,a binder, preferably polyvinyl alcohol, and a lubricant, preferablyglyceryl behenate. However, if necessary, additional inert excipientsconsistent with the objects of the invention may be added to the coreformulation. The additional inert excipients may be added to facilitatethe preparation and/or improve patient acceptability of the finalmodified-release bupropion hydrochloride dosage form as describedherein. The additional inert excipients are well known to the skilledartisan and can be found in the relevant literature, for example in theHandbook of Pharmaceutical Excipients. Non-limiting examples of suchexcipients include spray dried lactose, sorbitol, mannitol, and anycellulose derivative.

It is preferred that the granules to be compressed to form the core ofthe modified-release tablet of the invention described herein bemanufactured by the wet granulation process. Essentially, wetgranulation involves agitation of a powder (the active drug) byconvention in the presence of a liquid (the solution binder) followed bydrying. For forming the granules, which are to be eventually compressedinto the tablet cores, the bupropion hydrochloride is first granulated,preferably with a solution binder, in a granulator, preferably but notnecessarily a fluidized bed granulator such as for example a fluidizedbed granulator manufactured by Glatt (Germany) or Aeromatic(Switzerland). The binder, preferably polyvinyl alcohol, is firstdissolved or dispersed in a suitable solvent, preferably water. Thesolution binder is then top sprayed onto the drug in a granulator,preferably a fluidized bed granulator. Alternatively, granulation canalso be performed in a conventional or high shear mixer. If necessary,the additional inert excipients such as for example a filler can bemixed with the bupropion hydrochloride prior to the granulation step.

The granules formed are subsequently dried and then sieved prior toblending the granules with the lubricant. Preferably, the dried granulesare sieved through a 1.4 mm mesh screen. The sieved granules are thenblended with the lubricant, and if necessary, any other additional inertexcipients, which may improve processing of the modified-release tabletsof the invention. Blending of the granules with the lubricant, and ifnecessary, any additional inert excipients, such as for example aglidant, may be performed in a V-blender or any other suitable blendingapparatus. Glidants improve the flowability of the powder. This isespecially important during tablet production at high production speedsand during direct compaction. However, because the requirement foradequate flow is high, a glidant is often also added to a granulationbefore tabletting. The blended granules are subsequently pressed intotablets and are hereinafter referred to as tablet cores. Tablet corescan be obtained by the use of standard techniques and equipment wellknown to the skilled artisan. Ideally, but not necessarily, the tabletcores are obtained by a rotary press (also referred to as amulti-station press) fitted with suitable punches.

2. Tablet Coatings

The tablet cores are coated in two stages. The control-releasing coatingis applied directly onto the surface of the tablet cores and functionsto control the release of the pharmaceutically acceptable salt ofbupropion. The moisture barrier is applied directly onto the surface ofthe control-releasing coat to impede or retard the absorption ofmoisture

2.1 The Control-Releasing Coat

The control-releasing coat is a semi-permeable coat comprising awater-insoluble, water-permeable film-forming polymer, a plasticizer anda water-soluble polymer.

Non-limiting examples of water-insoluble, water-permeable film-formingpolymers useful for the control-releasing coat include cellulose ethers,cellulose esters, and polyvinyl alcohol. The preferred water-insoluble,water-permeable film forming polymers are the ethyl celluloses, and canbe selected from the group consisting of ethyl cellulose grade PR100,ethyl cellulose grade PR20 and any combination thereof. Ethyl cellulosegrade PR 100 is the preferred water-insoluble, water-permeable filmforming polymer. The amount of the water-insoluble water-permeablefilm-forming polymer may vary from about 1% to about 8% by weight of thetablet dry weight and preferably from about 2% to about 6% by weight ofthe tablet dry weight. For the 150 mg dose bupropion hydrochloridemodified-release tablets of the invention, the amount of water-insolublewater permeable film-forming polymer may vary from about 3% to about 6%by weight of the tablet dry weight. Preferably, the amount of thewater-insoluble water-permeable film-forming polymer is present at about6.3% by weight of the tablet dry weight. With respect to thecontrol-releasing coat itself, the amount of water-insolublewater-permeable film-forming polymer may vary from about 35% to about60% and by weight of the control-releasing coat dry weight. Preferably,the amount of water-insoluble water-permeable polymer is present atabout 50% by weight of the control-releasing coat dry weight. For the300 mg dose bupropion hydrochloride modified-release tablet of theinvention, the amount of water-insoluble water-permeable film-formingpolymer may vary from about 2% to about 5% by weight of the tablet dryweight. Preferably, the amount of water-insoluble water-permeable filmforming polymer is present at about 3.6% by weight of the tablet dryweight. With respect to the control-releasing coat itself, thewater-insoluble water-permeable film-forming polymer is present at about45% by weight of the control-releasing coat dry weight.

Plasticizers are generally added to film coating formulations to modifythe physical properties of the polymer to make it more usable. Theamount and choice of the plasticizer contributes to the hardness of atablet and may even affect its dissolution or disintegrationcharacteristics, as well as its physical and chemical stability. Oneimportant property of plasticizers is their ability to make a coatelastic and pliable, thereby decreasing the coat's brittleness.Non-limiting examples of plasticizers useful for the control-releasingcoat described herein include polyols, such as polyethylene glycol ofvarious molecular weights, organic esters, such as diethyl phthalate ortriethyl citrate, and oils/glycerides such as fractionated coconut oilor castor oil. The amount of plasticizer for the control-releasing coatmay vary in an amount from about 0.5% to about 2% by weight of thetablet dry weight. The preferred plasticizer is polyethylene glycol1450. For the 150 mg dose bupropion hydrochloride modified-releasetablet of the invention, the amount of plasticizer present in thecontrol-releasing coat may vary from about 1% to about 1.5% by weight ofthe tablet dry weight. Preferably, the amount of plasticizer is presentat about 1.5% by weight of the tablet dry weight. For the 300 mg dosebupropion hydrochloride modified-release tablet of the invention, theamount of plasticizer present may vary from about 0.5% to about 2% byweight of the tablet dry weight. For both the 150 mg and 300 mg dosageforms, the plasticizer is present preferably from about 6% to about 30%by weight of the control-releasing coat dry weight and more preferablyat about 12% by weight of the control-releasing coat dry weight.

Non-limiting examples of water-soluble polymers useful for thecontrol-releasing coat include polyvinylpyrrolidone, hydroxypropylmethylcellulose and hydroxypropyl cellulose. The preferred water-solublepolymer is polyvinylpyrrolidone the amount of which may vary from about1.5% to about 6% by weight of the tablet dry weight. With respect to thecontrol-releasing coat itself, the amount of water-soluble polymerpresent may vary from about 25% to about 55% by weight of thecontrol-releasing coat dry weight. For the 150 mg dose of the bupropionhydrochloride modified-release tablet of the invention, the amount ofwater-soluble polymer present may vary from about 3% to about 5% byweight of the tablet dry weight or from about 25% to about 50% by weightof the control-releasing coat dry weight. For the 300 mg dose of thebupropion hydrochloride modified-release tablet of the invention, theamount of water-soluble polymer present may vary from about 2% to about5% of the tablet dry weight and about 43% of the control-releasing coatdry weight.

The ratio of water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the 150 mg dose of themodified-release bupropion hydrochloride tablet of the inventiondescribed herein may vary from about 3:1:4 to about 5:1:3. The preferredratio is about 4:1:3. For the 300 mg dose of the modified-releasebupropion hydrochloride tablet of the invention described herein, theratio of the water-insoluble water-impermeable film-formingpolymer:plasticizer:water-soluble polymer may vary from about 7:2:6 toabout 19:5:18. The preferred ratio is about 13:4:12.

Generally, preparation and application of the control-releasing coat isas follows. The water-insoluble water-permeable film-forming polymer,preferably ethylcellulose, and the plasticizer, preferably polyethyleneglycol 1450, are dissolved in an organic solvent such as a mixture ofethyl alcohol and isopropyl alcohol. The plasticizer, preferablypolyvinyl pyrrolidone is next added until a homogenous mixture isachieved. The resulting control-releasing coat solution is then sprayedonto the tablet cores using a tablet coater, fluidized bed apparatus orany other suitable coating apparatus known in the art until the desiredweight gain is achieved. The tablet cores coated with thecontrol-releasing coat are subsequently dried before the moisturebarrier is applied.

The skilled artisan will appreciate that controlling the permeabilitycan control the release of the bupropion hydrochloride and/or the amountof coating applied to the tablet cores. The permeability of thecontrol-releasing coat, can be altered by varying the ratio of thewater-insoluble, water-permeable film-formingpolymer:plasticizer:water-soluble polymer and/or the quantity of coatingapplied to the tablet core. A more extended release is generallyobtained with a higher amount of water-insoluble, water-permeable filmforming polymer. The addition of other excipients to the tablet core mayalso alter the permeability of the control-releasing coat. For example,if it is desired that the tablet core further comprise an expandingagent, the amount of plasticizer in the control-releasing coat should beincreased to make the coat more pliable as the pressure exerted on aless pliable coat by the expanding agent would rupture the coat.Further, the proportion of the water-insoluble water-permeable filmforming polymer and water-soluble polymer may also have to be altereddepending on whether a faster or slower dissolution and/or releaseprofile is desired.

Depending on the dissolution or in-vivo release profile desired theweight gained after coating the tablet core with the control-releasingcoat might vary from about 3% to about 30% of the weight of the drytablet core. For the 150 mg dose modified-release bupropionhydrochloride tablet of the invention the weight gain may vary fromabout 13% to about 16% of the weight of the dry tablet core. Preferably,the weight gain is about 15% of the weight of the dry tablet core. Forthe 300 mg dose modified-release bupropion hydrochloride tablet of theinvention the weight gain may vary from about 8% to about 10% of theweight of the dry tablet core. Preferably, the weight gain is about 9%of the weight of the dry tablet core.

2.2 The Moisture Barrier

The moisture barrier is applied directly onto the control-releasing coatand comprises an enteric and/or an acrylic polymer, a permeationenhancer and optionally a plasticizer.

The enteric polymer is preferably an acrylic polymer. The acrylicpolymer is preferably a methacrylic acid copolymer type C[poly(methacrylic acid, methyl methacrylate) 1:1] available commerciallyunder the trade name Eudragit® (e.g. Eudragit L 30 D-55). Themethacrylic acid copolymer is present in an amount, which may vary fromabout 1% to about 3% of the tablet dry weight and from about 55% toabout 70% of the moisture barrier dry weight. For the 150 mg dose of themodified-release bupropion hydrochloride tablet of the invention, themethacrylic acid copolymer may vary from about 2% to about 3% of thetablet dry weight. Preferably, the amount of the methacrylic acidcopolymer is present at about 2.5% of the tablet dry weight. Withrespect to the moisture barrier itself, the amount of the methacrylicacid copolymer is present preferably from about 30% to about 90% byweight of the moisture barrier dry weight and more preferably at about66% of the moisture barrier dry weight. For the 300 mg dose of themodified-release bupropion hydrochloride tablet of the invention, theamount of the methacrylic acid copolymer may vary from about 1.5% toabout 3% of the tablet dry weight. Preferably, the amount of methacrylicacid copolymer is present at about 2% by weight of the tablet dryweight. With respect to the coating itself, the methacrylic acidcopolymer is present preferably from about 30% to about 90% of themoisture barrier dry weight and more preferably at about 66% of themoisture barrier dry weight for the 300 mg dose modified-release tabletof the invention.

It is known in the art that methacrylic acid copolymers tend to becomebrittle and therefore require a plasticizer. Non-limiting examples ofplasticizers useful for the control-releasing coat described hereininclude polyols, such as polyethylene glycol of various molecularweights, organic esters, such as diethyl phthalate or triethyl citrate,and oils/glycerides such as fractionated coconut oil or castor oil. Thepreferred plasticizer comprises a combination of triethyl citrate andpolyethylene glycol 1450. The ratio of triethyl citrate to polyethyleneglycol 1450 is about 1:2. The plasticizer is present in an amount, whichmay vary from about 0.2% to about 0.5% and preferably from about 0.2% toabout 0.4% of the tablet dry weight. The plasticizer is present at about0.35% of the tablet dry weight for the 150 mg tablet and from about 0.2%to about 0:4% of the tablet dry weight for the 300 mg tablet. Withrespect to moisture barrier itself, the plasticizer is presentpreferably from about 1% to about 30% by weight of the moisture barrierdry weight and more preferably at about 10% of the moisture barrier dryweight for both the 150 mg and 300 mg dose modified-release bupropionhydrochloride tablet of the invention. It is well known in the art thatdepending on the intended main function, excipients to be used intablets are subcategorized into different groups. However, one excipientcan affect the properties of a drug or the tablet as a whole in a seriesof ways, and many substances used in tablet formulations can thereforebe described as multifunctional. Thus, the polyethylene glycol 1450 usedin the plasticizer combination for the moisture barrier serves not onlyto increase the hydrophilicity of the moisture barrier, but also acts asa glidant.

In addition to the polyethylene glycol 1450, the permeation enhanceralso acts as a glidant and also increases the hydrophilicity of themoisture barrier. The permeation enhancer is hydrophilic substance andmay be selected from the group consisting of silicon dioxide, colloidalsilicon, lactose, hydrophilic polymers, sodium chloride, aluminum oxide,colloidal aluminum oxide, silica, microcrystalline cellulose and anycombination thereof. Silicon dioxide is the preferred permeationenhancer. The amount of permeation enhancer present may vary from about0.5% to about 1% by weight of the tablet dry weight and is about 25% byweight of the moisture barrier dry weight. For the 150 mg dosemodified-release bupropion hydrochloride tablet of the invention, thepermeation enhancer is present in an amount of about 0.9% of the tabletdry weight and from about 20% to about 40% and preferably about 25% byweight of the moisture barrier dry weight. For the 300 mg dosemodified-release bupropion hydrochloride tablet of the invention, thepermeation enhancer is present in an amount, which may vary from about0.5% to about 1% by weight of the tablet dry weight and is presentpreferably from about 20% to about 40% and preferably at about 25% byweight of the moisture barrier dry weight.

The ratio of the methacrylic acid copolymer:plasticizer:permeationenhancer is preferably about 13:2:5.

Generally, the preparation and application of the moisture barrierprocess is as follows. The plasticizer, preferably a combination ofpolyethylene glycol 1450 and triethyl citrate, is first added to waterand the mixture mixed to homogeneity. The methacrylic acid co-polymer,preferably Eudragit® L 30 D-55, is next sieved and added to theplasticizer mixture and mixed to homogeneity. In a separate containerthe permeation enhancer, preferably silicon dioxide is dissolved inwater until a homogeneous mixture is achieved. The plasticizer andmethacrylic acid copolymer mixture is then combined with the permeationenhancer solution and mixed to homogeneity. The resulting moisturebarrier solution is then sprayed onto the tablet cores coated with thecontrol-releasing coat using a tablet coater, fluidized bed apparatus orany other suitable coating apparatus known in the art until the desiredweight gain is achieved. The tablets coated with the moisture barrierare subsequently dried prior to packaging.

The moisture barrier is applied to the control-releasing coated tabletcores such that the weight gain is no more than about 6% and preferablyno more than about 2.5% of the tablet dry weight of both the 150 mg and300 mg modified-release bupropion hydrochloride tablets of theinvention. The amount of the moisture barrier applied does not renderthe bupropion hydrochloride modified release tablet described hereinresistant to gastric fluid and has no significant impact on the drugrelease characteristics.

The moisture barrier as used herein does not function as an entericcoat. Even though the methacrylic acid copolymer, Eudragit® L 30 D-55,is referenced and is used in enteric coating formulations in the art,its functionality is formulation dependent and on the quantity of thematerial applied. As is known in the art, an enteric coating is appliedwhere a drug may be destroyed or inactivated by gastric juice or wherethe drug may irritate the gastric mucosa. To meet the requirements foran enteric coat, the test as described in the USP (method A or B)stipulates that after 2 hours in acidic media (0.1N HCl), no individualvalues of at least six experiments exceed 10% of the active drugdissolved and not less than 75% dissolved at 45 minutes in pH 6.8. Themoisture barrier does not meet this requirement for the followingreasons even though the bupropion hydrochloride is not negativelyaffected in acidic media nor is it irritating the gastric mucosa: (1) toobtain enteric integrity with a film containing Eudragit® L 30 D-55, aweight gain of between about 6% to about 8% based on the dry polymer perdosage unit is recommended. The amount of Eudragit® L 30 D-55 solidapplied onto the control-releasing coated tablet cores is no more than6% and preferably no more than 2.5%, (2) if enteric integrity would berequired, the dissolution test for the finished product (i.e., themoisture barrier coated tablet cores) at the 2 hour time point would notstipulate a limit of no more than 20%, and (3) analytical testsperformed on the final two coat product indicate that the product doesnot meet all the test requirements as an enteric coated product asdefined by USP test methods. Since the moisture barrier is applieddirectly onto the control release coat, tests were conducted todetermine if the moisture barrier applied directly onto the immediaterelease tablet cores function as an enteric coat. Tests show that after1 hour more than 40% of the bupropion hydrochloride is released from thetablet cores in 0.1 N HCl and hence does not fall within the definitionof the USP for an enteric coat (see Example 2). The functionality of themoisture barrier was also confirmed by determining the moisture contentusing the Karl-Fischer (KF) test of the individually coated controlreleasing and moisture barrier coated tablet cores under acceleratedconditions (40° C.±2° C./75% RH±5% RH) in an open glass dish for 10 days(see Example 2). The results show that moisture content for thecontrol-releasing coated tablet cores is higher than for the moisturebarrier coated tablet cores. Cumulatively these data establish thefunctionality of the moisture barrier as a coat, which substantiallyimpedes or retards the absorption of moisture and not as an enteric coatas defined by the USP.

The tablet of the invention provides for an extended-release of thebupropion hydrochloride though no pore forming agent is present in theformulation. The above formulation also provides for a stable bupropionhydrochloride formulation such that after about 2 hours, no more thanabout 20%, preferably about 2% to about 18%, more preferably about 4% toabout 8%, and most preferably about 5% of the bupropion hydrochloridecontent is released, after about 4 hours, about 20% to about 45%,preferably about 21% to about 37%, more preferably about 28% to about34%, and most preferably about 32% of the bupropion hydrochloridecontent is released, after about 8 hours, about 40% to about 90%,preferably about 60% to about 85%, more preferably about 68% to about74%, and most preferably about 74% of the bupropion hydrochloridecontent is released and after about 16 hours no less than about 80%,preferably no less than about 93%, more preferably no less than about96%, and most preferably no less than about 99% of the bupropionhydrochloride content is released.

The positive impact on stability of the modified-release bupropionhydrochloride tablet of the formulation described herein is evident inthe tests performed to evaluate the total impurities present in eitherthe 150 mg or 300 mg dosage forms through 6 months under acceleratedconditions (40° C.±2° C./75% RH±5% RH) as well as through 12 months and18 months of long-term stability at 25° C.±2° C./60% RH±5% RH. Thestability tests showed reduced values (relative to Wellbutrin SR) intotal impurities in tablets.

In 7 count, 40 cc and 30 count, 100 cc HDPE bottles for both the 150 mgand 300 mg dosage strength modified-release tablets of the invention forexample, the total impurities present should be no more than about 2.5%by weight of the amount of bupropion hydrochloride in the tablet,preferably no more that about 1.5%, and most preferably no more thatabout 0.6% through at least 12 months of long-term stability at 25°C.+2° C./60% RH±5% RH. At 18 months of long-term-stability at 25° C.±2°C./60% RH±5% RH, the total impurities present should be no more thanabout 2.5% by weight of the amount of bupropion hydrochloride in thetablet, preferably no more than about 1.5%, and most preferably no morethan about 0.7% by weight of the amount of bupropion hydrochloride inthe tablet. Thus, the modified-release bupropion hydrochloride tabletaccording to the present invention contains at least about 95% w/w andmore preferably at least 98% or even at least 99% of undegradedbupropion hydrochloride after storage for 12 or 18 months of long-termstability under the humidity and temperature conditions usuallyencountered in pharmacies and medicine cabinets i.e. room temperatureand 35-60% humidity. Thus, when used in a pharmaceutical preparation forexample, a tablet, it will still retain at least 95% of its potency andpreferably at least 98% or even 99% of its potency after one year ofstorage at room temperature (15°-25° C.) at 35-60% humidity. For exampleif the tablet initially contains 300 mg bupropion hydrochloride (labeledamount) at time of preparation, after one-year storage at least 285 mgof bupropion hydrochloride and preferably at least 294 mg or more willremain in the tablet.

The KF moisture content and the total amount of impurities of bupropionhydrochloride for the 150 mg dosage strength tablets of the inventionwhen stored under accelerated conditions through at least 6 months forthe 7 count, 40 cc HDPE bottle configurations should be no more thanabout 1%. The same bottle and tablet configuration for the 300 mg dosagestrength stored under the same accelerated conditions should have a KFmoisture content of no more than about 1% and total impurities of nomore than about 0.6% through at least 6 months. The 150 mg tabletsstored in the 30 count, 100 cc HDPE bottle configuration should have aKF moisture content of no more than about 1% and total impurities of nomore than about 1.2% when stored under accelerated conditions through atleast 6 months. The 300 mg dosage strength tablets stored in the sameconfiguration under the same conditions for the same amount of timeshould have a KF moisture content of no more than about 1% and totalimpurities of no more than about 0.8%. When stored in an open glassdish, the KF moisture content of a 300 mg dosage strengthmodified-release tablet of the invention should be no more than about0.8% after 3 days and preferably no more than 0.45% after 10 days whenstored under accelerated conditions. When stored in tightly sealed glassbottles the KF moisture content should be no more than 0.45% after3-days and preferably no more than about 0.4% after 10 days.

The following examples illustrate the present invention and are notintended to limit the scope of the present invention.

EXAMPLE 1

1. Modified Release Tablet Formulations

Three different core formulations were prepared for each of the 150 mgand 300 mg modified release bupropion hydrochloride tablets as shown inTable 1: TABLE 1 CORE FORMULATION 150 mg 300 mg A B C A′ B′ C′Ingredients (mg/%)¹ (mg/%) (mg/%) (mg/%) (mg/%) (mg/%) Bupropion150/81.1  150/82.4  150/79  300/79 300/87.6   300/83.5 hydrochlorideBinder² 5.3/2.86 5.3/2.9  5.3/2.8  10.6/2.8 10.6/3.1   10.6/2.95Lubricant³ 4.7/2.54 4.7/2.58 4.7/2.46  9.4/2.48 9.4/2.74   9.4/2.61Purified water⁴ * * * * * * Total dry weight  160/86.48  160/87.91 160/83.77   320/84.43 320/93.47   320/89.02 of core¹The mg/% values represent the proportion of the ingredient in relationto the tablet dry weight²Polyvinyl alcohol³Glyceryl behenate (Compritol 888 ATO)⁴Evaporated during drying

The water is first heated to 60±5° C. The binder (polyvinyl alcohol) isnext dissolved in the water to homogeneity and then passed through a 0.7mm mesh screen and allowed to cool to a temperature of no more thanabout 30° C. Bupropion hydrochloride is placed in the top sprayingchamber of a fluidized bed apparatus, such as for example a Glatt GPCG1fluidized bed apparatus. The solution binder (i.e., the polyvinylalcohol solution) is sprayed onto the bupropion hydrochloride, with thein-process parameters shown in Table 2: TABLE 2 GRANULATION PROCESSPARAMETERS Air flow (m³/h) 2000-2500 Pump flow rate (g/min) 150-250Inlet temperature 50° C.-70° C. Outlet temperature 30° C.-50° C.Spraying pressure (Bar) 3-5 Product temperature 35° C.-50° C.

Once the granulation is completed, the granules are allowed to dry andthen cooled to a temperature of no more than about 35° C. The bupropionhydrochloride granules are then passed through a 1.4 mm mesh sieve.

The lubricant (glyceryl behenate) together with the sieved granules isthen blended in a V-Blender until the mixture is uniformly mixed. Theresulting mixture is pressed into tablet cores using a rotary tabletpress (Manesty Unipress) with an average hardness from about 8 Sc toabout 25 Sc and an average thickness from about 3.9 mm to about 4.5 mmfor the 150 mg tablet cores, and an average hardness from about 12 Sc toabout 33 Sc, and an average thickness from about 4.8 mm to about 5.4 mmfor the 300 mg tablet cores. The friability of the tablet cores for bothdosage strengths is no more than 0.8%. The tablet cores are then coatedwith the control-releasing coat formulations shown in Table 3: TABLE 3CONTROL-RELEASING COAT FORMULATION 150 mg 300 mg A B C A′ B′ C′Ingredients (mg/%¹) (mg/%) (mg/%) (mg/%) (mg/%) (mg/%) Water-insolublewater- 10.26/5.55  5.63/3.1  12/6.28   19/5.01 6.71/1.96 13.05/3.63permeable film forming polymer² Water soluble polymer³ 5.64/3.05 7.5/4.19/4.7 18.06/4.77  6.37/1.86 12.40/3.45 Plasticizer⁴  2.1/1.14 1.88/1.033/1.6 5.16/1.36 1.82/0.53  3.55/0.99 Denatured Ethyl * * * * * * Alcohol95%⁵ Isopropyl Alcohol 99%⁵ * * * * * * Dry weight of control-   18/9.73  15/8.24  24/12.56 42.22/11.14 14.9/4.35   29/8.07 releasing coat¹The % values represent the proportion of the ingredient in relation tothe tablet dry weight²Ethylcellulose 100 (Ethocel ®)³Polyvinylpyrrolidone (Kollidon ® 90F)⁴Polyethylene Glycol 1450 (Carbowax ®)⁵Evaporated during drying

The plasticizer (polyethylene glycol 1450) followed by thewater-insoluble water permeable film-forming polymer (ethylcellulose100) is added to a portion of a mixture of the denatured ethyl alcoholand the isopropyl alcohol. Once mixed, the water-soluble polymer isgradually added to the above mixture to avoid large particles orclumping. The solution is mixed to homogeneity. The remainder of thedenatured ethyl alcohol and isopropyl alcohol is then added to thecoating mixture and mixing is continued until a homogeneous solution isachieved. The coating solution is then passed through a DeBeeHomogenizer (nozzle size 7, process pressure at 8500±2000 psi and backpressure at 1000±250 psi). The homogenized coating solution is thensprayed onto the tablet cores in a tablet coater (O'Hara 36 Side Vent)with the process parameters shown in Table 4: TABLE 4 CONTROL-RELEASINGCOAT PROCESS PARAMETERS Process Parameters 150 mg tablet cores 300 mgtablet cores Pan Speed (rpm)  5-15  5-15 Exhaust Air Temperature 25 ± 4025 ± 40 (° C.) Inlet Air Temperature (° C.) 300 ± 60  30 ± 60 Spray Rate(g/min) 160-400 160-400 Atomizing Air Pressure (psi) 30-50 30-50 PatternAir Pressure (psi) 20-40 20-40 Air Flow (CFM)  800-1100  800-1100

Coating of the tablet cores with the control-releasing coat solution iscontinued until a weight gain of about 24 mg (wet coating range of about22 to about 26 mg) and a weight gain of about 29 mg (wet coating rangeof about 27 to about 31 mg) is achieved for the 150 mg and 300 mg tabletcores respectively. Once the desired weight gain is reached, the coatingis stopped and the coated tablet cores are dried at an inlet airtemperature of about 35±2° C. with a pan speed set at about 2 rpm. Thedried and cooled coated tablet cores are next coated with the moisturebarrier formulation shown in Table 5: TABLE 5 MOISTURE BARRIERFORMULATION 150 mg 300 mg A B C A′ B′ C′ Ingredients (mg/%)¹ (mg/%)(mg/%) (mg/%) (mg/%) (mg/%) Methacrylic Acid Co- 4.59/2.48 4.59/2.524.59/2.40 10.99/2.9  4.88/1.42 6.86/1.91 Polymer² PlasticizerCombination (D = 0.46 (D = 0.46 (D = 0.46 (D = 1.1 (D = 0.49 (D = 0.69(D + E)³ E = 0.23) E = 0.23) E = 0.23) E = 0.56) E = 0.25) E = 0.35)0.69/0.38 0.69/0.38 0.69/0.36 1.66/0.44 0.74/0.21 1.04/0.29 Permeationenhancer⁴ 1.72/0.93 1.72/0.95 1.72/0.90 4.11/1.08 1.83/0.53 2.57/0.71Purified Water⁵ * * * * * * Dry weight of moisture   7/3.78   7/3.85  7/3.66 16.76/4.42  7.45/2.18 10.47/2.91  barrier¹The mg/% values represent the total proportion of the ingredient inrelation to the tablet dry weight²poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit ® L 30 D-55)³D = Polyethylene Glycol 1450 (Carbowax ®), E = Triethyl Citrate⁴Silicon Dioxide (Syloid ® 244)⁵Evaporated during drying

The plasticizer combination, preferably polyethylene glycol 1450 andtriethyl citrate, are first dissolved in a portion of the purified waterand mixed to homogeneity. While the plasticizer solution is being mixed,the methacrylic acid copolymer, preferably Eudragit® L 30 D-55, ispassed through a 0.3 mm mesh screen in a separate container. Theplasticizer solution is next added to the methacrylic acid copolymer andmixed until a homogenous solution is achieved. While the methacrylicacid copolymer/plasticizer solution is being mixed, the permeationenhancer, preferably, silicon dioxide, is dissolved in the remainder ofthe water and mixed with a high shear mixer until the suspension ishomogenous. The final moisture barrier solution is obtained by mixingthe permeation enhancer solution with the methacrylic acidcopolymer/plasticizer mixture. The homogenized moisture barrier solutionis then sprayed onto the control release coated tablet cores in acoating pan with the process parameters as shown in Table 6: TABLE 6MOISTURE BARRIER PROCESS PARAMETERS Process Parameters 150 mg tabletcores 300 mg tablet cores Pan Speed (rpm)  5-15  5-15 Exhaust AirTemperature 25-40 25-40 (° C.) Inlet Air Temperature (° C.) 30-60 30-60Spray Rate (g/min) 160-400 160-400 Atomizing Air Pressure (psi) 30-5030-50 Pattern Air Pressure (psi) 20-40 20-40 Air Flow (CFM)  800-1100 800-1100

The moisture barrier is applied until a weight gain of about 7 mg (wetcoating tablet range of about 6.3 to about 7.7 mg) and about 10.5 mg(wet coating tablet range of about 9.5-11.5 mg) is achieved for the 150mg and 300 mg dose modified release tablets respectively. Once thedesired weight gain is reached, the coating is stopped and the coatedtablets are dried at an inlet air temperature of about 35±2° C. with apan speed set at about 2 rpm.

The coated tablets are finally printed with suitable indicia usingsuitable black ink, such as for example Opacodeg S-1-8090 black ink,using a tablet printer (Print International).

The dissolution profile for each of the three 150 mg and 300 mg doseswas determined under the following dissolution conditions:

-   -   Medium: 900 ml, 0.1N HCl    -   Method: USP Type I Apparatus (150 mg dose)/USP Type II Apparatus        (300 mg dose), at 75 rpm and 37° C.

The results are presented in Table 7 as the mean percent release of thetotal bupropion hydrochloride content in the coated tablets: TABLE 7Time 150 mg 300 mg (Hrs) B C A B′ C′ A′ 0 0 0 0 0 0 0 1 1.7 0.1 0.3 15 10.15 2 21.2 4.2 6.4 33 9.5 3.5 3 40.6 19.5 17.5 48.5 23.5 11.5 4 56.235.1 28.7 62.5 36.5 20 5 69.2 49 39.7 73.5 48 29 6 80.1 61.4 49.9 8358.5 38 7 88.1 72 56.7 90 67.5 46 8 93.1 80.9 68.7 94.5 75.5 54 9 95.788.1 77.6 97 82 62 10 97.1 92.6 84.6 98 87 69.5 11 98 95.1 89.7 99 90.576.5 12 98.7 96.7 92.7 99.5 93.5 82.5 13 99 97.7 94.6 100 95 87 14 99.498.6 95.9 100 96 91 15 99.6 99.2 96.6 100.5 96.5 93.5 16 99.9 99.6 97.2100.5 97.5 95 17 100 99.9 97.6 100.5 98 96.5 100.5 99 97 101 99 97.5 10199 98.5 101 100 98.5 101 100 99 101 99.5 99.5 101 100 99.5

The mean dissolution profile for the three different 150 mg and 300 mgmodified release bupropion hydrochloride tablets is shown in FIGS. 1Aand 1B respectively. Formulation C and C′ for the 150 mg and 300 mgdosage forms were selected for all further tests and manufacturing.

2. Stability of the Modified Release Tablet Formulations

The formulations are free of a stabilizer. To determine the stability ofthe bupropion hydrochloride in the absence of stabilizer, stabilitytests were conducted both under accelerated conditions over 6 months at40° C.±2° C./75% RH±5% RH and under long-term conditions over 12 and 18months at 25° C.±2° C./60% RH±5% RH. At the end of the specified timeperiod, the tablets were analyzed for impurities resulting from thedegradation of bupropion hydrochloride by HPLC. The degradation productsincluded those listed in the USP (26^(th) edition, pg 281) and any otherpeaks that appeared on the chromatogram. The results of the stabilityanalysis under both accelerated and long-term condition for both the 150mg and 300 mg dosage forms is shown in Tables 8, 9 and 10: TABLE 8Accelerated Conditions (40° C. ± 2° C./75 ± 5% RH) 150 mg¹ 300 mg¹ TimeTotal Total Total Total (months) Moisture² Impurities³ Moisture²Impurities³ Moisture² Impurities³ Moisture² Impurities³ 1 0.67 0.63 0.930.63 0.7 0.50 0.57 0.63 3 0.6 0.80 0.8 0.86 0.7 0.70 0.67 0.84 6 1.01.09 1.0 1.22 1.0 0.98 0.9 1.20¹Moisture and Impurity values are an average of three lots²KF Moisture content (%)³Total impurities derived from break down of bupropion hydrochloride asa % of bupropion hydrochloride present at start of analysis

TABLE 9 12 months of long-term stability (25° C. ± 2° C./60% RH ± 5% RH)Amt. in Tablets Acceptable Limits Data Derived at 12 months TotalImpurities 2.5% 1.5% 0.56%

TABLE 10 8 months of long-term stability (25° C. ± 2° C./60% RH ± 5% RH)Amt. in Tablets Acceptable Limits Data Derived at 18 months TotalImpurities 2.5% 1.5% 0.65%

The stability data to 48 months were evaluated by statistical expiryanalysis for each modified-release tablet dosage strength. Expiry plotsare presented in FIGS. 2A and 2B. The “data driven” specifications werederived by assessing the level of the upper confidence intervalprojected to 48 months.

EXAMPLE 2

1. The Moisture Barrier is not an Enteric Coat

The purpose of this study was to show that the modified releasebupropion hydrochloride tablets of the invention are not enteric coated.The modified release formulation is based on a tablet core comprisingbupropion hydrochloride, a binder and a lubricant. The tablet core iscoated with a control-releasing coat, which functions to control therelease of the bupropion hydrochloride. The control-releasing coatedtablet cores are subsequently coated with a moisture barrier, whichsubstantially impedse or retards absorption of moisture.

The release of the drug was measured spectrophotometrically by atwo-stage dissolution procedure using USP enteric coating dissolutionconditions method B (Basket at 75 rpm) to evaluate the tablet integrity.The results of the tests are shown in Tables 11 and 12: TABLE 11 AcidStage: % dissolved of 300 mg Time modified release bupropion HCl tablets(hr) V1 V2 V3 V4 V5 V6 Mean SD 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 0.10.0 0.6 0.5 1.2 0.2 0.3 0.7 2 3.1 1.7 9.7 7.3 10.2 7.2 6.5 3.5

TABLE 12 Buffer Stage: % dissolved of 300 mg Time modified releasebupropion HCl tablets (hr) V1 V2 V3 V4 V5 V6 Mean SD 1 21.8 20.3 19.221.2 21.6 20.3 20.7 1.0 2 35.2 34.6 32.4 34.9 33.9 32.9 34.0 1.1 3 45.045.1 43.3 45.5 42.8 43.5 44.2 1.2 4 53.2 55.0 51.1 53.1 50.6 51.2 52.31.7 5 59.6 64.6 57.2 59.5 58.0 57.4 59.4 2.8 6 64.7 70.7 62.2 65.1 66.762.7 65.3 3.1 7 69.1 75.1 66.6 69.4 71.7 67.1 69.8 3.2 8 74.4 78.1 70.173.0 75.8 71.8 73.9 2.9 9 78.8 80.1 73.2 75.8 77.6 75.7 76.9 2.5 10 81.681.5 75.5 77.7 78.6 77.8 78.8 2.4 11 83.2 82.5 77.2 79.3 79.5 79.1 80.12.3 12 84.1 83.1 78.0 80.6 80.0 79.9 81.0 2.3 13 84.6 83.7 78.4 81.380.2 80.4 81.4 2.3 14 84.9 84.0 78.6 81.5 80.2 80.8 81.7 2.4

At acidic pH (0.1N HCl), about 7% of the bupropion hydrochloride isreleased within 2 hours, however at pH 6.8 about 21% of the bupropionhydrochloride is released within 1 hour. Accordingly, the modifiedrelease tablet of the invention does not meet the USP requirement of anenteric-coated tablet i.e., after 2 hours in acidic media (0.1N HCl) noindividual values exceed 10% dissolved active drug and not less than 75%dissolved at 45 minutes in pH 6.8 buffer.

The functionality of the moisture barrier as a non-enteric coat wasfurther shown by directly coating 150 mg tablet cores with the moisturebarrier. Table 13 shows that the dissolution results (the first 2 hoursin acidic medium) do not comply with the USP requirements for anenteric-coated tablet.

-   -   Medium: 900 ml 0.1 N HCl

Method: USP Apparatus type I at 75 rpm at 37° C. TABLE 13 Time %Bupropion Hydrochloride dissolved (hr) V1 V2 V3 V4 V5 V6 Mean SD % RSD 00.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 45.6 41.7 39.8 46.5 42.4 50.1 44.33.8 8.5 2 75.5 73.7 69.1 76.4 71.3 84.6 75.1 5.4 7.2 3 93.9 98.4 95.193.4 89.4 100.9 95.2 4.0 4.2 4 99.1 99.1 102.2 102.0 99.0 102.5 100.61.7 1.7 5 99.5 99.1 102.2 103.5 101.7 102.5 101.4 1.8 1.7

A buffer test was not performed due to the high release in the acidicmedium.

2. The Moisture Barrier Functions to Substantially Impede or Retard theAbsorption of Moisture.

The functionality of the moisture barrier as a coat which substantiallyimpedes or retards the absorption of moisture was confirmed bydetermining the Karl-Fischer moisture content of eithercontrol-releasing coated tablet cores or moisture barrier coated tabletcores for the 300 mg tablet cores. The preparation for the formulationsis as described in Example 1. The respective coated tablets were placedseparately under accelerated conditions (40° C.±2° C./75% RH±5% RH) inan open glass dish for 10 days. As shown in Table 14, the moisturecontent for the control-releasing coated tablet cores are higher thanfor the moisture barrier coated tablet cores. TABLE 14 % KF MoistureContent Control-releasing Coated Tablet 0.7 Cores Moisture barrierCoated Tablet Cores 0.45

The data presented in Tables 13 and 14 demonstrate that the moisturebarrier does not function as an enteric coat as defined by the USP.Instead, the data demonstrate the functionality of the moisture barrieras a coat, which substantially impedes or retards the absorption ofmoisture.

EXAMPLE 3

The objective of this study was to investigate the dosage strengthequivalency of the following test 150 mg and 300 mg product strengths ofBupropion HCl modified-release tablets under fasting conditions. Atwo-way, crossover, open-label, single-dose, fasting, dosage strengthequivalency study of two strengths (150 mg and 300 mg) of bupropion HClmodified-release tablets of the invention was conducted. Themodified-release tablets of the invention were administered once dailyin normal healthy non-smoking male and female subjects.

The study design involved a 2-period, 2-treatment, single-dose crossoverdesign under fasting conditions. The study periods were separated by a3-week washout period. A total of 36 subjects (19 Male, 17 Female)enrolled for the study of which 35 of the subjects (19 Male, 16 Female)completed the study. Subjects were administered the followingtreatments:

A) 2×150 mg q.d. modified-release bupropion hydrochloride tablets of theinvention administered orally with 240 mL of ambient temperature waterfollowing an overnight fast of at least 10 hours.

B) 1×300 mg q.d. modified-release bupropion hydrochloride tablets of theinvention administered orally with 240 mL of ambient temperature waterfollowing an overnight fast of at least 10 hours.

The graphical mean plasma-concentration (ng/ml) profiles of bupropionand its metabolites hydroxybupropion, bupropion threoamino alcohol, anderythroamino alcohol over a 120-hour time period after administration ofthe 2×150 mg once daily and the 1×300 mg once daily dosage forms areshown in FIGS. 3A-D respectively.

Tables 15a-d provide the mean (±SD) pharmacokinetic data for bupropionfollowing administration of the 2×150 mg dosage strength tabletadministered once daily or the 300 mg dosage strength tabletadministered once daily: TABLE 15a (Bupropion) Bupropion HCl 2 × 150 mgBupropion HCl 1 × Modified 300 mg Modified- Pharmacokinetic ReleaseTablets of the Release Tablets Parameter Invention of the Invention(mean ± SD) (n = 35) (n = 35) AUC_(0-t) (ng · hr/mL) 1648.85 ± 475.341676.61 ± 474.09 AUC_(0-inf) (ng · hr/mL) 1702.69 ± 489.30 1728.34 ±478.43 C_(max) (ng/mL) 150.11 ± 37.22 146.88 ± 47.61 T_(max) (hours) 4.99 ± 0.76  5.20 ± 0.88 T_(1/2) (hours) 22.70 ± 7.42 21.84 ± 7.35K_(el) (hour⁻¹)  0.036 ± 0.017  0.037 ± 0.018 MRT (hours) 22.28 ± 5.5022.92 ± 5.50

TABLE 15b (Hydroxybupropion) Bupropion HCl 2 × 150 mg Bupropion HClModified1 × 300 mg Pharmacokinetic Release Tablets of the ModifiedRelease Tablets Parameter Invention of the Invention (mean ± SD) (n =35) (n = 35) AUC_(0-t) (ng · hr/mL) 22506.34 ± 9372.50 22380.32 ±8740.47 AUC_(0-inf) (ng · hr/mL)  23634.19 ± 10373.91 23498.81 ± 9584.58C_(max) (ng/mL)  492.97 ± 182.28  479.23 ± 172.64 T_(max) (hours) 11.66± 5.64 14.06 ± 5.10 t_(1/2) (hours) 24.01 ± 4.85 24.09 ± 4.57 K_(el)(hour⁻¹)  0.030 ± 0.007  0.030 ± 0.006 MRT (hours) 39.93 ± 6.94 41.18 ±7.07 M/P ratio 13.4886 ± 5.3391 13.2966 ± 5.0489

TABLE 15c (Bupropion Threoamino Alcohol) Bupropion HCl 2 × 150 mgBupropion HCl Modified 1 × 300 mg Pharmacokinetic Release Tablets of theModified Release Tablets Parameter Invention of the Invention (mean ±SD) (n = 35) (n = 35) AUC_(0-t) (ng · hr/mL) 7548.05 ± 3627.79 7262.88 ±3083.24 AUC_(0-inf) (ng · hr/mL) 9428.73 ± 4982.30 9091.33 ± 3926.24C_(max) (ng/mL) 173.22 ± 60.80  162.24 ± 58.97  T_(max) (hours) 7.76 ±2.65 8.47 ± 3.41 t_(1/2) (hours) 50.47 ± 16.76 51.51 ± 16.83 K_(el)(hour⁻¹) 0.015 ± 0.005 0.015 ± 0.005 MRT (hours) 69.31 ± 22.44 71.33 ±21.93 M/P ratio 5.4378 ± 2.1088 5.2774 ± 2.0478

TABLE 15d (Bupropion Erythroamino Alcohol) Bupropion HCl 2 × 150 mgBupropion HCl Extended 1 × 300 mg Pharmacokinetic Release Tablets of theExtended Release Tablets Parameter Invention of the Invention (mean ±SD) (n = 35) (n = 35) AUC_(0-t) (ng · hr/mL) 1508.79 ± 601.87 1441.85 ±495.53 AUC_(0-inf) (ng · hr/mL) 1702.71 ± 777.29 1613.65 ± 623.69C_(max) (ng/mL) 28.88 ± 6.54 27.52 ± 6.67 T_(max) (hours) 13.03 ± 3.4815.24 ± 4.15 t_(1/2) (hours) 32.15 ± 8.65 32.12 ± 9.22 K_(el) (hour⁻¹) 0.023 ± 0.007  0.023 ± 0.006 MRT (hours)  51.60 ± 12.65  52.34 ± 13.44M/P ratio  0.9985 ± 0.3678  0.9527 ± 0.3863

The relative (2×150 mg (q.d.) vs. 1×300 mg (q.d.)) bioavailabilityanalysis results for AUC_(0-inf), AUC_(0-t), and C_(max), transformedusing the natural logarithm under fasting conditions is summarized inTable 16 for bupropion and its metabolites: TABLE 16 Ratio of Intra-Ratio of Geometric Subject Geometric Intra-Subject Parameter 90% C.I.Means CV 90% C.I. Means CV Bupropion Hydroxybupropion AUC_(0-t)93.96%-102.76%  98.26% 11.07% 94.42%-106.07% 100.08% 14.37% AUC_(0-inf)93.97%-102.88%  98.32% 11.19% 94.23%-105.81%  99.85% 14.32% C_(max)97.77%-110.30% 103.84% 14.90% 97.76%-108.17% 102.84% 12.51% BupropionThreoamino Alcohol Bupropion Erythroamino Alcohol AUC_(0-t)96.66%-109.16% 102.72% 15.03% 96.83%-110.30% 103.34% 16.09% AUC_(0-inf)94.87%-108.57% 101.49% 16.66% 97.09%-110.89% 103.76% 16.42% C_(max)100.06%-114.03%  106.82% 16.16% 99.41%-111.26% 105.17% 13.91%

The data shows that both the 150 mg dosage strength tablet given as twotablets once daily and 300 dosage strength tablet given once daily ofthe modified-release tablets of the invention as described herein and inExample 1 are equivalent to each other in terms of their pharmacokineticparameters for bupropion and its metabolites.

EXAMPLE 4

A four-way, crossover, open-label, single-dose, fasting and food-effectcomparative bioavailability study of bupropion hydrochloridemodified-release 150 mg tablets as described herein and in Example 1 andZyban® 150 mg tablets in normal healthy non-smoking male and femalesubjects were conducted. This study was designed to evaluate the rateand extent of absorption of bupropion in the fed and fasted state afteradministration of 150 mg dosage strength bupropion hydrochloridemodified-release tablets as described herein and in Example 1. Inparallel, the rate and extent of absorption of bupropion in the fed andfasted state after administration of 150 mg dosage strength Zyban®tablets was also evaluated in this study.

The study design followed a 2-period, 2-treatment, single-dose crossoverdesign under fasting and fed conditions. The study periods wereseparated by a 2-week washout period. A total of 35 subjects (24 Male,11 Female) were enrolled in the study of which 32 of the subjects (22Male, 10 Female) completed the study. Subjects were administered thefollowing treatments:

A) 150 mg q.d. modified-release bupropion hydrochloride tablets of theinvention under fasting conditions,

B) 150 mg q.d. modified-release bupropion hydrochloride tablets of theinvention under fed conditions,

C) 150 mg q.d. Zyban® tablets under fasting conditions, and

D) 150 mg q.d. Zyban® tablets under fed conditions.

The graphical mean plasma-concentration (ng/ml) profiles of bupropionand its metabolites hydroxybupropion, bupropion threoamino alcohol, anderythroamino alcohol over a 72-hour time period after administration ofthe 1×150 mg once daily modified-release tablets of the invention andthe 1×150 mg once daily dosage form of Zyban® are shown in FIGS. 4A-E.

Table 17 provides the mean (±SD) pharmacokinetic data for bupropionfollowing administration of the 150 mg dosage strength modified-releasetablets of the invention or the commercially available prior art Zyban®tablets under fasting and fed conditions for bupropion and itsmetabolites: TABLE 17 Geometric Mean Arithmetic Mean ± SD (% CV)Bupropion HCl Bupropion HCl 150 mg 150 mg Modified Modified ReleaseTablets of Zyban ® 150 mg Zyban ® 150 mg Release Tablets the InventionTablets Tablets Pharmacokinetic (Fasted) (Fed) (Fasted) (Fed) Parameter(n = 32) (n = 32) (n = 32) (n = 32) Bupropion AUC_(0-t) (ng · hr/mL) 825.1787  882.1834  840.5866 1002.9491 864.56 ± 259.86 918.59 ± 271.21881.48 ± 270.64 1048.50 ± 306.63  (30.06) (29.52) (30.70) (29.24)AUC_(0-inf) (ng · hr/mL)  886.1622*  926.4870*  884.2148*  1043.8802*923.43 ± 263.01 966.18 ± 290.02 929.01 ± 291.01 1092.41 ± 326.05 (28.48) (30.02) (31.32) (29.85) C_(max) (ng/mL)  78.2884  73.1637 92.1115  124.3873 81.78 ± 24.47 75.75 ± 19.77 96.96 ± 31.38 128.81 ±32.03  (29.93) (26.10) (32.37) (24.87) T_(max) (hours)† 5.13 ± 1.13 6.59± 2.18 3.04 ± 0.77 3.88 ± 1.01 (22.02) (33.10) (25.41) (25.99) t_(1/2)(hours)† 18.17 ± 6.35* 19.26 ± 6.77* 19.88 ± 5.91* 19.48 ± 5.45* (34.97)(35.15) (29.75) (27.99) K_(el) (hour⁻¹)†  0.044 ± 0.018*  0.041 ± 0.017* 0.039 ± 0.017*  0.039 ± 0.015*  (41.996)  (42.214)  (42.096)  (38.386)MRT_(0-inf) (hours)†  4.81 ± 2.38*  5.18 ± 2.99*  4.69 ± 2.25*  4.34 ±2.00* (49.43) (57.81) (47.93) (46.08) Hydrobupropion AUC_(0-t) (ng ·hr/mL) 10745.045  10939.113  11514.933  12975.263  12611.91 ± 8151.69 12604.70 ± 7739.11  12976.49 ± 6817.46  14679.97 ± 8184.51  (64.63)(61.40) (52.54) (55.75) AUC_(0-inf) (ng · hr/mL) 11209.310  11383.270 11910.790  13397.186*  13034.17 ± 8207.41  13049.55 ± 7933.08  13344.28± 6863.47  15129.56 ± 8370.60  (62.97) (60.79) (51.43) (55.33) C_(max)(ng/mL)  222.2716  230.4191  294.8008  301.9918 245.61 ± 119.94 252.46 ±112.93 316.89 ± 125.90 325.85 ± 131.69 (48.83) (44.73) (39.73) (40.42)T_(max) (hours)† 15.22 ± 6.14  15.38 ± 4.35  6.04 ± 1.18 7.19 ± 2.91(40.32) (28.31) (19.56) (40.49) t_(1/2) (hours)† 25.19 ± 5.90  25.26 ±5.98  25.37 ± 6.14  25.68 ± 5.70* (23.42) (23.67) (24.21) (22.18) K_(el)(hour⁻¹)† 0.029 ± 0.007 0.029 ± 0.008 0.029 ± 0.008  0.028 ± 0.006* (25.285)  (26.635)  (27.142)  (22.223) MRT_(0-inf) (hours)† 5.78 ± 4.175.78 ± 3.20 4.84 ± 2.22  4.01 ± 1.87* (72.15) (55.43) (45.85) (46.57)M/P ratio† 3.851 ± 1.097 4.029 ± 1.210 3.874 ± 1.214 4.556 ± 1.360Bupropion Threoamino Alcohol AUC_(0-t) (ng · hr/mL) 4223.4179 4397.53754376.0423 5042.7155 4686.42 ± 2736.63 4969.37 ± 3229.17 4832.84 ±2671.85 5478.16 ± 2694.10 (58.39) (64.98) (55.29) (49.18) AUC_(0-inf)(ng · hr/mL) 4466.6770 4702.2669 4644.3189 5346.5138 5006.42 ± 3088.855360.00 ± 3691.31 5147.80 ± 2897.63 5853.85 ± 3083.18* (61.70) (68.87)(56.29) (52.67) C_(max) (ng/mL)  81.8673  87.4966  107.2111  124.786088.43 ± 37.68 93.97 ± 36.82 112.12 ± 34.64  130.65 ± 40.68  (42.61)(39.18) (30.90) (31.13) T_(max) (hours)† 10.03 ± 3.62  11.94 ± 3.39 5.76 ± 1.02 5.38 ± 0.95 (36.12) (28.39) (17.65) (17.66) t_(1/2) (hours)†49.27 ± 14.83 50.94 ± 15.39 51.44 ± 14.06  52.82 ± 14.82* (30.10)(30.22) (27.34) (28.05) K_(el) (hour⁻¹)† 0.015 ± 0.005 0.015 ± 0.0050.014 ± 0.004  0.014 ± 0.004*  (30.287)  (30.636)  (26.839)  (31.030)MRT_(0-inf) (hours)† 15.81 ± 12.98 17.89 ± 13.50 16.52 ± 12.41  18.23 ±14.02* (82.07) (75.49) (75.11) (76.92) M/P ratio† 3.851 ± 1.097 4.029 ±1.210 3.874 ± 1.214 4.556 ± 1.360 Bupropion Erythroamino AlcoholAUC_(0-t) (ng · hr/mL)  615.3554  662.8840  666.6066  766.3201 675.24 ±321.49 722.75 ± 341.87 716.66 ± 300.64 823.24 ± 320.87 (47.61) (47.30)(41.95) (38.98) AUC_(0-inf) (ng · hr/mL)  711.3752  754.6092  750.7705 839.2428 768.15 ± 333.66 816.35 ± 372.52 802.32 ± 315.77  893.65 ±330.20* (43.44) (45.63) (39.36) (36.95) C_(max) (ng/mL)  13.6946 14.6158  17.2653  18.1560 14.17 ± 3.85  15.04 ± 3.56  17.55 ± 3.23 18.50 ± 3.84  (27.14) (23.69) (18.39) (20.76) T_(max) (hours)† 15.57 ±4.65  14.88 ± 3.09  6.85 ± 1.92 7.88 ± 3.83 (29.90) (20.74) (28.04)(48.57) t_(1/2) (hours)† 29.14 ± 8.77  30.39 ± 10.17 29.69 ± 9.37  31.38 ± 10.74* (30.09) (33.47) (31.57) (34.23) K_(el) (hour⁻¹)† 0.026 ±0.007 0.025 ± 0.008 0.026 ± 0.009  0.024 ± 0.007*  (28.240)  (31.201) (34.415)  (30.060) MRT_(0-inf) (hours)† 17.10 ± 6.30  16.94 ± 9.04 15.10 ± 5.65  15.09 ± 6.62* (36.87) (53.39) (37.44) (43.89) M/P ratio†3.851 ± 1.097 4.029 ± 1.210 3.874 ± 1.214 4.556 ± 1.360*n = 31†Expressed as Arithmetic Mean ± SD (% CV)

The relative (modified-release tablets of the invention fasting vs. fed)bioavailability analysis results for AUC_(0-inf), AUC_(0-t), and C_(max)transformed using the natural logarithm under both fasting and fastingconditions is summarized in Table 18 for bupropion and its metabolites:TABLE 18 Intra- Ratio of Subject Ratio of Intra- Parameter 90% C.I.Means CV 90% C.I. Means Subject CV Bupropion Hydroxybupropion AUC_(0-t)101.74%-112.23% 106.852% 11.786%  95.30%-109.76% 102.275% 16.971%AUC_(0-inf) 100.18%-109.60% 104.788% 10.533%  95.48%-108.95% 101.993%15.844% C_(max)  86.58%-100.13%  93.107% 17.470%  97.20%-111.36%104.043% 16.336% Bupropion Threoamino Alcohol Bupropion ErythroaminoAlcohol AUC_(0-t)  98.77%-109.74% 104.108% 12.646% 101.02%-114.99%107.780% 15.564% AUC_(0-inf) 100.03%-110.79% 105.274% 12.269%100.49%-112.09% 106.132% 13.127% C_(max) 100.41%-113.77% 106.884%14.998% 101.23%-112.49% 106.712% 12.662%

The data in Table 18 show that the bioavailability of bupropion and itsmetabolites does not show a food effect i.e., the modified-releasetablets of the invention containing bupropion hydrochloride arebioequivalent in the presence or absence of food as evidenced by thefact that the 90% CI of the ratio of the geometric means for theAUC_(0-inf) (and the AUC_(0-t) when appropriate) and C_(max) in thefasting vs. fed state fall within the FDA suggested limits of 80-125%.

EXAMPLE 5

A two-way, crossover, open-label, single-dose, food-effect, comparativebioavailability study of the 300 mg dosage strength bupropionhydrochloride modified-release tablets of the invention in normalhealthy non-smoking male and female subjects.

The study was designed to evaluate the effect of food on the rate andextent of absorption of the once-daily 300 mg dosage strength bupropionhydrochloride modified-release tablets of the invention undersingle-dose conditions. The study design followed a 2-period,2-treatment, single-dose crossover design under fasting and fedconditions. The study periods were separated by a 2-week wash outperiod. A total of 36 subjects (26 Male, 10 Female) were enrolled in thestudy of which 32 of the subjects (23 Male, 9 Female) completed thestudy. Subjects were administered the following:

A) 1×300 mg modified-release tablet after a 1 hour fast.

B) 1×300 mg modified-release tablet after complete intake of a high fatbreakfast.

The graphical mean plasma-concentration (ng/ml) profiles of bupropionand its metabolites hydroxybupropion, bupropion threoamino alcohol, anderythroamino alcohol over a 120-hour time period after administration ofthe 1×300 mg once daily modified-release tablets of the invention underfed and fasting conditions are shown in FIGS. 5A-D respectively.

Table 19 provides mean (±SD) pharmacokinetic data for bupropion and itsmetabolites following administration of the 300 mg dosage strengthmodified-release tablets of the invention under fasting and fedconditions: TABLE 19 Bupropion HCl 300 mg Bupropion HCl 300 mg ModifiedRelease Tablets Modified Release Tablets (Fed) (Fasting) Pharmacokinetic(n = 31) (n = 31) Parameter Mean ± SD Mean ± SD Bupropion AUC_(0-t) (ng· hr/mL) 1775.45 ± 530.77 1628.38 ± 511.15 AUC_(0-inf) 1832.54 ± 548.501678.36 ± 521.18 (ng · hr/mL) C_(max) (ng/mL) 138.36 ± 42.35 151.35 ±48.87 T_(max) (hour)  6.16 ± 1.84  5.16 ± 0.86 t_(1/2) (hour) 21.76 ±5.85 21.21 ± 6.17 K_(el) (hour⁻¹)  0.035 ± 0.011  0.036 ± 0.012 MRT(hour) 22.56 ± 4.60 21.58 ± 4.23 Hydroxybupropion AUC_(0-t) (ng · hr/mL)19733.51 ± 9411.52 18938.84 ± 8387.21 AUC_(0-inf)  20886.13 ± 10230.6919852.73 ± 9049.54 (ng · hr/mL) C_(max) (ng/mL)  449.05 ± 181.73  409.79± 154.84 T_(max) (hour) 14.32 ± 3.18 13.71 ± 5.15 t_(1/2) (hour) 24.11 ±5.21 23.95 ± 4.84 K_(el) (hour⁻¹)  0.030 ± 0.007  0.030 ± 0.007 MRT(hour) 42.03 ± 7.60 41.08 ± 6.13 M/P Ratio 10.5919 ± 3.8325 11.3178 ±4.6281 Bupropion Threoamino Alcohol AUC_(0-t) (ng · hr/mL)  9769.69 ±6136.11  9032.19 ± 6595.77 AUC_(0-inf) 13280.57 ± 9398.23 11696.29 ±9018.00 (ng · hr/mL) C_(max) (ng/mL) 208.39 ± 98.15 182.52 ± 99.62T_(max) (hour) 12.26 ± 3.36  9.94 ± 4.84 t_(1/2) (hour)  55.09 ± 17.66 55.25 ± 20.72 K_(el) (hour⁻¹)  0.014 ± 0.004  0.014 ± 0.004 MRT (hour) 79.10 ± 25.10  78.60 ± 28.28 M/P Ratio  6.9435 ± 3.8129  6.6417 ±3.4215 Bupropion Erythroamino Alcohol AUC_(0-t) (ng · hr/mL) 1803.45 ±693.19 1634.56 ± 741.60 AUC_(0-inf)  2116.01 ± 1026.23 1867.74 ± 971.96(ng · hr/mL) C_(max) (ng/mL) 35.80 ± 9.13 31.03 ± 9.97 T_(max) (hour)14.74 ± 2.71 14.16 ± 3.85 t_(1/2) (hour)  35.23 ± 12.03  33.89 ± 11.02K_(el) (hour⁻¹)  0.021 ± 0.006  0.022 ± 0.006 MRT (hour)  57.78 ± 17.49 54.75 ± 14.45 M/P Ratio  1.1322 ± 0.3876  1.0947 ± 0.3952

The relative (Fed vs. Fasting) bioavailability analysis results forAUC_(0-inf), AUC_(0-t), and C_(max) transformed using the naturallogarithm under both fasting and fasting conditions for bupriopion andits metabolites is summarized in Table 20: TABLE 20 Ratio of Intra-Ratio of Geometric Subject Geometric Intra-Subject Parameter 90% C.I.Means CV 90% C.I. Means CV Bupropion Hydroxybupropion AUC_(0-t)104.00%-116.57% 110.10% 13.21%  96.27%-111.84% 103.76% 17.36%AUC_(0-inf) 104.18%-116.49% 110.16% 12.93%  97.03%-112.72% 104.58%17.35% C_(max)  84.49%-100.86% 92.31% 20.50% 103.44%-116.91% 109.97%14.17% Bupropion Threoamino Alcohol Bupropion Erythroamino AlcoholAUC_(0-t) 104.31%-121.18% 112.42% 17.36% 104.06%-123.56% 113.39% 19.89%AUC_(0-inf) 104.15%-125.65% 114.39% 20.59% 105.26%-126.61% 115.44%21.39% C_(max) 110.61%-124.96% 117.57% 14.12% 110.14%-126.40% 117.99%15.94%

The data in Table 20 show that the bioavailability of bupropion and itsmetabolites from the 300 mg dosage strength modified-release bupropionhydrochloride tablets of the invention do not show a food effect asevidenced by the fact that the 90% CI of the ratio of the geometricmeans for the AUC_(0-inf) (and the AUC_(0-t) when appropriate) andC_(max) in the fed vs. fasted state fall within the FDA suggested limitsof 80-125%.

EXAMPLE 6

A two-way, crossover, steady state, multiple-dose, open-label, fasting,comparative bioavailability study of a once-daily bupropionhydrochloride 300 mg modified-release tablet of the invention versus theimmediate release thrice daily Wellbutrin® 100 mg tablets in normalhealthy non-smoking male and female subjects was conducted. This studywas designed to evaluate the bioavailability of a once daily 300 mgdosage strength of the modified-release tablets of the inventionrelative to the commercially available prior art thrice daily immediaterelease Wellbutrin® tablets under steady-state, fasting conditions.

The study was designed as a 2-period, 2-treatment, dose escalated,multiple-dose crossover study under fasting conditions with a 2-weekwashout period between the two study periods. A total of 40 subjects (27Males, 13 Females) were enrolled in the study of which 30 subjects (22Males, 8 Females) completed the study. Subjects were administered thefollowing dosing regimen:

A) Wellbutrin® 100 mg tablets were administered orally at 0.0 hours(starting at 7:00 AM) on Days 1, 2, and 3 (b.i.d.) with 240 ml ofambient temperature water following an overnight fast of at least 10hours. All subjects also received a second dose of 1 Wellbutrin® 100 mgtablets at 12.0 hours with 240 ml of ambient temperature water after afast of at least 1 hour. On days 4-13, subjects received one 300 mgdosage strength bupropion hydrochloride modified-release tablet of theinvention at 0.0 hours (starting at 7: AM) with 240 ml of ambienttemperature water following an overnight fast of at least 10 hours.

B) Wellbutrin® 100 mg tablets were administered orally at 0.0 hours(starting at 7:00 AM) on Days 1, 2, and 3 (b.i.d.) with 240 ml ofambient temperature water following an overnight fast of at least 10hours. All subjects also received a second dose of 1 Wellbutrin® 100 mgtablet at 12.0 hours with 240 ml of ambient temperature water after afast of at least 1 hour. On days 4-13, subjects received 1 Wellbutrin®100 mg tablet at 0.0 hours (starting at 7:00 AM) with 240 ml of ambienttemperature water, following an overnight fast of at least 10 hours. Allsubjects then received a second dose of 1 Wellbutrin® 100 mg tablet at6.0 hours with 240 ml of ambient temperature water following a fast ofat least 1 hour. All subjects also received a third dose of 1Wellbutrin® 100 mg tablet at 12.0 hours with 240 ml of ambienttemperature water, following a fast of at least 1 hour.

The graphical mean plasma-concentration (ng/ml) profiles of bupropionand its metabolites hydroxybupropion, bupropion threoamino alcohol, anderythroamino alcohol over the study period after administration of the1×300 mg once daily modified-release tablets of the invention and theWellbutrin® 3×100 mg tablets are shown in FIGS. 6A-E respectively.

Table 21 provides the mean (±SD) pharmacokinetic data for bupropionfollowing administration of the once daily 300 mg dosage strengthmodified-release tablet of the invention or the thrice-dailycommercially available prior art Wellbutrin® 100 mg tablet: TABLE 21Bupropion HCl 300 mg Modified Release Tablets of the Wellbutrin ® 100 mgInvention Tablets Pharmacokinetic (n = 30) (n = 30) Parameter (mean ±SD) (mean ± SD) Bupropion AUC_(0-τ) (ng · hr/mL) 1612.04 ± 490.27 1791.98 ± 483.43  C_(max) (ng/mL) 167.50 ± 46.56  175.40 ± 56.03 C_(min) (ng/mL) 27.64 ± 10.73 34.06 ± 12.49 T_(max) (hours) 4.90 ± 0.891.60 ± 0.58 Degree of Fluctuation 212.56 ± 39.42  189.98 ± 38.99  (%)C_(ave) (ng/mL) 67.17 ± 20.43 74.67 ± 20.14 Degree of Swing (%) 554.59 ±193.21 439.58 ± 141.64 M/P ratio 12.92 ± 5.31  12.61 ± 5.11 Hydroxybupropion AUC_(0-τ) (ng · hr/mL) 20824.77 ± 7423.56  22456.08 ±6889.20  C_(max) (ng/mL) 1095.64 ± 385.06  1156.34 ± 339.34  C_(min)(ng/mL) 722.23 ± 281.76 800.90 ± 262.97 T_(max) (hours) 7.30 ± 2.45 2.47± 0.83 Degree of Fluctuation 44.34 ± 16.57 40.78 ± 31.24 (%) C_(ave)(ng/mL) 867.70 ± 309.32 935.67 ± 287.05 Degree of Swing (%) 54.65 ±22.48 49.19 ± 40.60 M/P ratio 7.01 ± 1.84 6.91 ± 1.81 BupropionThreoamino Alcohol AUC_(0-τ) (ng · hr/mL) 10987.88 ± 3193.09  12051.42 ±3107.48  C_(max) (ng/mL) 585.36 ± 155.83 629.81 ± 138.84 C_(min) (ng/mL)364.42 ± 122.60 415.71 ± 122.32 T_(max) (hours) 7.83 ± 2.15 2.49 ± 0.81Degree of Fluctuation 50.47 ± 17.22 45.25 ± 21.80 (%) C_(ave) (ng/mL)457.83 ± 133.05 502.14 ± 129.48 Degree of Swing (%) 65.68 ± 26.11 56.34± 29.48 M/P ratio 1.39 ± 0.44 1.36 ± 0.43 Bupropion Erythroamino AlcoholAUC_(0-τ) (ng · hr/mL) 2145.70 ± 615.22  2353.73 ± 645.40  C_(max)(ng/mL) 109.07 ± 29.98  119.37 ± 26.82  C_(min) (ng/mL) 76.51 ± 25.6985.59 ± 26.63 T_(max) (hours) 8.37 ± 2.04 2.40 ± 0.66 Degree ofFluctuation 38.11 ± 15.25 38.90 ± 33.91 (%) C_(ave) (ng/mL) 89.40 ±25.63 98.07 ± 26.89 Degree of Swing (%) 46.04 ± 20.70 46.18 ± 43.72 M/Pratio 1.39 ± 0.44 1.36 ± 0.43

The relative (modified-release tablets of the invention v. Wellbutrin®)bioavailability analysis results for AUC_(0-τ) and C_(max) for bupropionand its metabolites transformed using the natural logarithm issummarized in Table 22: TABLE 22 Ratio of Intra- Ratio of Intra-SubjectParameter 90% C.I. Means Subject CV 90% C.I. Means CV BupropionHydroxybupropion AUC_(0-τ) 86.14%-92.64% 89.33% 8.27% 87.00%-95.42%91.11% 10.49% C_(max)  91.08%-103.00% 96.86% 13.97% 85.98%-99.90% 92.68%17.04% Bupropion Threoamino Alcohol Bupropion Erythroamino AlcoholAUC_(0-τ) 87.17%-94.21% 90.63% 8.82% 87.32%-94.66% 90.91% 9.16% C_(max)87.42%-97.28% 92.22% 12.13% 84.84%-95.89% 90.20% 13.91%

The data in Tables 21 and 22 show that a 300 mg dosage strengthmodified-release tablet of the invention administered once daily isbioequivalent to the 100 mg dosage strength immediate releaseWellbutrin® administered thrice daily.

EXAMPLE 7

A two-way, steady state, crossover, open-label, multiple-dose, fasting,comparative bioavailability study of the 300 mg modified-releasebupropion hydrochloride tablets of the invention versus the commerciallyavailable prior art 150 mg Zyban® product in normal healthy non-smokingmale and female subjects was carried out. The study was designed tocompare the bioavailability of the 300 mg q.d. dosage form of themodified-release bupropion hydrochloride tablets of the inventionagainst the commercially available prior art 150 mg b.i.d. Zyban®tablets.

The study design followed a 2-period, 2-treatment, multiple-dosecrossover design under fasting conditions. The study periods wereseparated by a 2-week washout interval. A total of 54 subjects (40 Male,14 Female) were enrolled in the study of which 49 of the subjects (37Male, 12 Female) completed the study. Subjects were administered 150 mgq.d. Zyban® tablets from days 1-3 of the study. Days 4-17 were followedby:

A) 300 mg q.d. modified-release bupropion hydrochloride tablets of theinvention.

B) 1.50 mg b.i.d. Zyban® tablets.

The graphical mean plasma-concentration (ng/ml) profiles of bupropionand its metabolites hydroxybupropion, bupropion threoamino alcohol, anderytlroamino alcohol over the study period after administration of the1×300 mg once daily modified-release tablets of the invention and the2×150 mg (b.i.d.) Zyban® tablets under fasting conditions are shown inFIGS. 7A-E respectively.

Table 23 provides the mean (±SD) pharmacokinetic data for bupropionfollowing administration of the once daily 300 mg dosage strengthmodified-release tablet of the invention or the commercially availableprior art 150 mg b.i.d. Zyban® tablet: TABLE 23 Geometric MeanArithmetic Mean (% CV) 300 mg Dosage Strength Modified Release BupropionZyban ® Pharmacokinetic HCl Tablets of the Invention 150 mg TabletsParameter (n = 49) (n = 49) AUC_(0-τ) (ng · hr/mL) 1412.4767 1561.96511464.21 1617.72 (28.12) (26.94) C_(max) (ng/mL) 143.9693 135.9517 148.81141.65 (26.10) (28.36) C_(min) (ng/mL) 23.1224 25.3277 24.50 26.85(35.46) (35.28) T_(max) (hours)* 4.92 3.23 (17.03) (31.63) Degree ofFluctuation 207.65 171.85 (%)* (20.47) (19.27) Degree of Swing (%)*551.15 449.59 (37.98) (26.79) C_(ave) (ng/mL)* 61.01 67.41 (28.12)(26.94) MRT (hours)* 9.63 10.23 (6.57) (2.90) Hydroxybupropion AUC_(0-τ)(ng · hr/mL) 19688.697 21984.655 21255.88 23792.58 (38.44) (39.17)C_(max) (ng/mL) 1035.5625 1114.0976 1111.28 1200.37 (36.14) (38.41)C_(min) (ng/mL) 669.3453 775.6489 731.59 847.91 (41.72) (42.12) T_(max)(hours)* 6.61 4.26 (34.52) (35.36) Degree of Fluctuation 44.42 36.96(%)* (35.50) (50.36) Degree of Swing (%)* 56.77 46.22 (47.41) (75.49)C_(ave) (ng/mL)* 885.66 991.36 (38.44) (39.17) MRT(hours)* 11.43 11.53(2.87) (1.93) M/P Ratio* 14.538 14.684 (43.310) (43.323) BupropionThreoamino alcohol AUC_(0-τ) (ng · hr/mL) 9040.7734 110398.325 9638.6411100.02 (37.34) (38.42) C_(max) (ng/mL) 494.6250 542.8864 524.91 582.74(37.35) (44.35) C_(min) (ng/mL) 285.9451 339.2713 311.93 370.23 (43.69)(45.18) T_(max) (hours)* 7.74 4.45 (35.60) (35.77) Degree of Fluctuation55.31 47.10 (%)* (32.09) (32.50) Degree of Swing (%)* 75.80 61.76(43.62) (40.19) C_(ave) (ng/mL)* 401.61 462.50 (37.34) (38.42) MRT(hours)* 11.63 11.74 (2.85) (1.76) M/P Ratio* 6.609 6.830 (29.472)(26.491) Bupropion Erythroamino alcohol AUC_(0-τ) (ng · hr/mL) 1784.51152033.8788 1875.33 2125.14 (31.95) (30.18) C_(max) (ng/mL) 92.4622101.5651 97.12 105.63 (32.17) (28.49) C_(min) (ng/mL) 61.3442 71.686365.30 75.83 (36.05) (34.19) T_(max) (hours)* 8.31 4.74 (38.42) (42.77)Degree of Fluctuation 41.87 35.10 (43.18) (37.78) Degree of Swing (%)*53.00 43.04 (54.46) (50.13) C_(ave) (ng/mL)* 78.14 88.15 (31.95) (30.18)MRT (hours)* 11.73 11.73 (2.63) (1.87) M/P Ratio* 1.298 1.334 (27.168)(25.504)*Expressed as arithmetic means (% CV)

The relative (modified-release tablets of the invention v. Zyban®)bioavailability analysis results for AUC_(0-τ), C_(max) and C_(min)transformed using the natural logarithm for bupropion and itsmetabolites is summarized in Table 24: TABLE 24 BupropionHydroxybupropion Ratio of Ratio of Intra- 90% Geometric Intra-SubjectGeometric Subject Parameter C.I. Means CV 90% C.I. Means CV AUC_(0-τ)87.19%-93.93% 90.50% 10.98% 85.87%-93.26% 89.49% 12.17% C_(max) 99.25%-113.46% 106.12% 19.73% 89.02%-97.00% 92.93% 12.66% C_(min)85.77%-97.00% 91.21% 18.14% 82.22%-90.34% 86.19% 13.88% BupropionThreoamino Alcohol Bupropion Erythroamino Alcohol Intra- Intra- 90%Ratio of Subject Ratio of Subject Parameter C.I. Means CV 90% C.I. MeansCV AUC_(0-τ) 83.91%-90.09% 86.94% 10.47% 84.48%-91.09% 87.72% 11.11%C_(max) 86.76%-95.78% 91.16% 14.59% 86.95%-95.44% 91.10% 13.73% C_(min)80.45%-88.16% 84.22% 13.49% 81.61%-89.60% 85.51% 13.77%

The data in Tables 23 and 24 show that a 300 mg (q.d.) dosage strengthmodified-release bupropion hydrochloride tablet of the invention isbioequivalent to the 150 mg b.i.d sustained-release commerciallyavailable prior art Zyban® tablet.

EXAMPLE 8 (COMPARATIVE EXAMPLE)

A 150 mg and 300 mg bupropion hydrochloride formulation was prepared astaught in U.S. Pat. No. 6,143,327 and the pharmacokinetic parameters andrelative bioavailability data assessed for bioequivalency. Theproportions of the components in the core, first and second coatformulations used are as shown in Table 25: TABLE 25 150 mg 300 mgComponents Mg % of core mg % of core CORE Bupropion HCl 150.00 93.75300.00 93.75 Binder¹ 5.30 3.31 10.6 3.31 Lubricant² 4.70 2.94 9.40 2.94Purified Water³ 110.00 * 220.00 * Total core weight 160.00 100 320.00100.00 FIRST COAT Water-insoluble water 10.96 60.8 14.40 60.00%permeable film forming polymer⁴ Water-soluble polymer⁵ 4.70 26.10 6.4726.96 Plasticizer⁶ 2.34 13.01 3.13 13.04 Ethyl Alcohol³ 190.00 *230.50 * Isopropyl Alcohol 99%³ 10.00 * 12.35 * Total dry first coat18.00 100.00 24.00 100.00 weight SECOND COAT Methacrylic Acid 7.75 63.0011.66 63.02 Copolymer⁷ Glidant⁸ 2.30 18.70 3.45 18.65 Plasticizer⁹ 2.2518.30 3.39 18.32 Purified water³ 48.00 * 72.20 * Total dry second coat12.30 100.00 18.50 100.00 weight¹Polyvinyl Alcohol²Glyceryl behenate (Compritol 888 ATO)³Evaporated during drying⁴Ethyl cellulose 100 Premium (Ethocel ®)⁵Polyvinylpyrrolidone (Kollidon ® 90F)⁶Polyethylene Glycol 1450 (Carbowax ®)⁷poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit ® L 30 D-55)⁸Plasticizer is a combination of polyethylene glycol 1450 and triethylcitrate in a ratio of 2:1⁹Silicon Dioxide (Syloid ® 244)

The tablets were manufactured as taught by the '327 patent.

A pilot three-way multiple-dose open-label fasting comparativebioavailability study of bupropion hydrochloride tablets (2×150 mg q.d.)made according to the '327 patent (the ‘327 patent formulation’) versusthe commercially available Zyban® sustained-release tablets (1×150 mgb.i.d.) and Wellbutrin® tablets (t.i.d.) in normal healthy smoking andnon-smoking male volunteers was conducted. The purpose of the study wasto evaluate the relative bioavailability of bupropion hydrochloride 150mg of the 327 formulation (2×150 mg q.d.) relative to Zyban® 150 mgsustained-release tablets (1×150 mg b.i.d) and Wellbutrin® 100 mgtablets (1×100 mg t.i.d.) under single dose or steady-state fastingconditions.

Table 26 shows the mean (±SD) plasma concentration-time profiles forbupropion (ng/ml) under single dose conditions: TABLE 26 Sample 2 × 150mg (q.d.) Zyban Wellbutrin ® tablet Time tablet of the ′327 150 mg SRtablets 100 mg (3 × 100 mg (hours) patent (A) (1 × 150 mg b.i.d.) (B)t.i.d) (C) 0.0 11.71 ± 3.55  8.25 ± 2.74 30.01 ± 17.82 1.0 11.08 ± 2.90 53.87 ± 14.58 113.91 ± 40.96  2.0 12.95 ± 4.38  75.96 ± 13.83 104.04 ±20.62  4.0 60.60 ± 24.59 83.71 ± 12.49  58.45 ± 12.90 5.0 ND ND 45.92 ±10.65 6.0 98.23 ± 31.28 64.03 ± 13.95 85.54 ± 80.91 7.0 ND ND 104.45 ±39.11  8.0 82.63 ± 23.84 41.69 ± 7.81  ND 9.0 ND ND 76.79 ± 15.73 11.0ND ND 50.28 ± 15.09 12.0 59.47 ± 18.45 21.50 ± 4.50  110.38 ± 71.29 13.0 ND 51.03 ± 34.38 120.69 ± 32.81  14.0 ND 84.04 ± 41.74 ND 15.0 NDND 75.30 ± 20.36 16.0 ND 86.15 ± 37.20 58.53 ± 15.44 18.0 32.46 ± 9.52 55.48 ± 13.29 ND 20.0 ND ND 33.45 ± 7.40  24.0 20.21 ± 5.28  27.81 ±7.77  24.14 ± 6.03 

Table 27 provides the mean (±SD) pharmacokinetic data for bupropionfollowing administration of the tablets shown in Table 25: TABLE 27Pharmaco- kinetic 327 Parameter formulation Zyban ® Wellbutrin ® (mean ±SD) (n = 15) (n = 15) (n = 15) AUC₀₋₂₄ 1154.65 ± 244.28 1301.05 ± 214.941622.89 ± 318.02 (ng · hr/mL) C_(max) (ng/mL) 103.77 ± 28.13 112.68 ±37.06 163.10 ± 56.84 T_(max) (hrs)  6.40 ± 1.88 11.07 ± 5.85  6.87 ±5.60

The relative bioavailability analysis results for AUC₀₋₂₄ (ng·hr/ml),and C_(max) (ng/ml) shown in Table 27, transformed using the naturalalgorithm is summarized in Table 28: TABLE 28 AUC₀₋₂₄ C_(max) Ratio ofIntra- Ratio of Intra- Geometric Subject Geometric Subject Parameter 90%C.I. Means C.V. 90% C.I. Means C.V. 327 78%-99% 88% 23.65%  78%-111% 93%31.44% formulation vs. Zyban ® 327 formulation vs. 63%-80% 71% 38.79%54%-76% 64% 52.35% Wellbutrin ®

Table 29 shows the mean (±SD) steady-state plasma concentration-timeprofiles for bupropion (ng/ml) for the tablet composition shown in Table25: TABLE 29 Sample 2 × 150 mg Zyban 150 mg SR Wellbutrin ® tablet Time(q.d.) tablet tablets (1 × 150 mg 100 mg (3 × 100 mg (hours) of the ′327patent b.i.d.) t.i.d) 0.0 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.0 11.71± 3.55  8.25 ± 2.74 30.01 ± 17.82 0.0 20.21 ± 5.28  27.81 ± 7.77  24.14± 6.03  0.0 22.22 ± 5.80  34.12 ± 8.51  27.11 ± 8.31  0.0 21.58 ± 6.21 32.70 ± 9.94  27.33 ± 8.79  0.0 23.44 ± 8.31  31.96 ± 8.83  28.71 ±11.05 1.0 21.47 ± 7.06  64.22 ± 18.93 112.09 ± 29.65  2.0 24.37 ± 8.77 90.76 ± 18.63 116.66 ± 27.01  4.0 87.61 ± 36.30 94.97 ± 19.30 61.94 ±16.35 5.0 ND ND 49.43 ± 13.56 6.0 101.39 ± 25.48  73.35 ± 17.94 85.34 ±52.23 7.0 ND ND 112.05 ± 46.38  8.0 77.06 ± 16.40 52.56 ± 11.74 ND 9.0ND ND 87.11 ± 23.77 11.0 ND ND 55.49 ± 17.50 12.0 58.88 ± 16.23 31.23 ±9.05  115.93 ± 53.59  13.0 ND 58.01 ± 21.81 117.74 ± 39.87  14.0 ND105.36 ± 42.68  ND 15.0 ND ND 74.33 ± 17.77 16.0 ND 93.55 ± 23.49 60.45± 14.56 18.0 34.69 ± 8.82  65.80 ± 14.61 ND 20.0 ND ND 39.86 ± 12.5524.0 23.30 ± 6.75  33.15 ± 9.39  29.49 ± 10.09 48.0 8.80 ± 4.20 12.02 ±4.84  11.11 ± 4.68  72.0 4.61 ± 2.60 5.75 ± 3.06 5.59 ± 2.75 96.0 2.25 ±1.82 3.03 ± 2.01 2.35 ± 1.45 120.0 1.01 ± 1.12 1.43 ± 1.44 1.35 ± 1.53

Table 30 shows the mean (±SD) pharmacokinetic data for bupropion understeady state conditions following administration of the tablets shown inTable 25: TABLE 30 Pharmaco- kinetic Parameter 327 formulation Zyban ®Wellbutrin ® (mean ± SD) (n = 15) (n = 15) (n = 15) AUC₀₋₂₄ 1251.45 ±257.24 1554.77 ± 293.70 1728.31 ± 374.54 (ng · hr/mL) C_(max) (ng/mL)112.24 ± 26.42 119.77 ± 27.76 156.19 ± 32.27 T_(max) (hrs)  5.33 ± 1.2311.47 ± 5.04  9.00 ± 4.14

The relative bioavailability analysis results for AUC₀₋₂₄ (ng·hr/ml),and C_(max) (ng/ml) shown in Table 30, transformed using the naturalalgorithm is summarized in Table 31: TABLE 31 AUC₍₀₋₂₄₎ C_(max) Ratio ofIntra- Ratio of Intra- Geometric Subject Geometric Subject Parameter 90%C.I. Means C.V. 90% C.I. Means C.V. 327 71%-91% 80% 20.06%  82%-108% 94%22.65% formulation vs Zyban ® 327 64%-82% 73% 20.06% 62%-82% 72% 22.65%formulation vs Wellbutrin ®

The pharmacokinetic and relative bioavailability data show that the 90%CI for the formulation as taught in the '327 patent does not fall withinthe FDA suggested 80%-125% range for a product to be bioequivalent.Accordingly, the data show that the '327 patent formulation is notbioequivalent to the commercially available Zyban®/Wellbutrin® SR orWellbutrin® tablets.

1. A modified-release tablet comprising: (i) a core comprising aneffective amount of a pharmaceutically acceptable salt of bupropion, andconventional excipients; (ii) a first control-releasing coat surroundingsaid core; and (iii) a moisture barrier surrounding said firstcontrol-releasing coat, wherein the modified-release tablet isbioequivalent and exhibits a dissolution profile such that after about 2hours no more than about 20% of the bupropion content is released, afterabout 4 hours about 15% to about 45% of the bupropion content isreleased, after about 8 hours about 40% to about 90% of the bupropioncontent is released and after about 16 hours no less than about 80% ofthe bupropion content is released.
 2. The modified-release tablet ofclaim 1 wherein said moisture barrier does not function as an entericcoating as defined by a USP test which requires for an entericlayer-coated tablet, when placed in 0.1N HCl for one hour, that thetotal amount of the drug released from the core does not exceed 10% andnot less than 75% of the drug is released at 45 minutes in pH 6.8buffer.
 3. The modified-release tablet of claim 2 or 3 when saidmoisture barrier is comprised of an enteric polymer, a plasticizer and apermeation enhancer.
 4. The modified-release tablet of claim 2 or 3wherein the application of the moisture barrier to the control-releasingcoated tablet results in a total weight gain of no more than about 6%relative to the dry tablet weight.
 5. The modified-release tablet ofclaim 2 wherein the application of the moisture barrier to thecontrol-releasing coated tablet results in a total weight gain of nomore than about 2.5% relative to the dry tablet weight.
 6. Themodified-release tablet of claim 3 wherein the enteric polymer is anacrylic polymer.
 7. The modified-release tablet of claim 6 wherein saidacrylic polymer is a methacrylic acid copolymer type C.
 8. Themodified-release tablet of claim 3, which comprises about 150 mg of saidpharmaceutically acceptable salt of bupropion, and the amount of saidenteric polymer ranges from 1% to 3% of the dry tablet weight andcomprises 55% to 70% of the moisture barrier dry weight.
 9. Themodified-release tablet of claim 3, which comprises about 300 mg of saidpharmaceutically acceptable salt of bupropion, and the amount of saidenteric polymer ranges from 1.5% to 3.0% of the dry tablet weight andcomprises from 30% to 90% of the moisture barrier dry weight.
 10. Themodified-release tablet of claim 8 wherein said enteric polymer is amethacrylic acid copolymer type C.
 11. The modified-release tablet ofclaim 9 wherein said enteric polymer is a methacrylic acid copolymertype C.
 12. The modified-release tablet of claim 10 wherein the polymeris Eudragit L 30 D-55.
 13. The modified-release tablet of claim 11wherein said polymer is Eudragit L 30 D-55.
 14. The modified-releasetablet of any one of claims 1-13 wherein said tablet exhibits adissolution profile such that after about 2 hours about 2% to about 18%of the bupropion content is released, after about 4 hours about 21% toabout 37% of the bupropion content is released, after about 8 hoursabout 60% to about 85% of the bupropion content is released and afterabout 16 hours no less than about 93% of the bupropion content isreleased.
 15. The modified-release tablet of claim 14 wherein saidtablet exhibits a dissolution profile such that after about 2 hoursabout 4% to about 8% of the bupropion content is released, after about 4hours about 28% to about 34% of the bupropion content is released, afterabout 8 hours about 68% to about 74% of the bupropion content isreleased and after about 16 hours no less than about 96% of thebupropion content is released.
 16. The modified-release tablet of claim15 wherein said tablet exhibits a dissolution profile such that afterabout 2 hours about 5% of the bupropion content is released, after about4 hours about 32% of the bupropion content is released, after about 8hours about 74% of the bupropion content is released and after about 16hours no less than about 99% of the bupropion content is released. 17.The modified-release tablet of claim 16 wherein said pharmaceuticallyacceptable salt of bupropion is bupropion hydrochloride.
 18. Themodified-release tablet of claim 17 wherein said bupropion is present atleast about 94% by weight of the core.
 19. The modified-release tabletof any one of claims 1-18 wherein said conventional excipients furthercomprise a binder and a lubricant.
 20. The modified-release tablet ofclaim 19 wherein said binder is present from about 1% to about 6% byweight of the core dry weight.
 21. The modified-release tablet of claim20 wherein said binder is present at about 3% by weight of the core dryweight.
 22. The modified-release tablet of claim 21 wherein said binderis selected from the group consisting of modified starch, gelatin,polyvinylpyrrolidone, cellulose derivatives, polyvinyl alcohol and anycombination thereof.
 23. The modified-release tablet of claim 22 whereinsaid binder is polyvinyl alcohol.
 24. The modified-release tablet ofclaim 19 wherein said lubricant is present from about 1% to about 6% byweight of the core dry weight.
 25. The modified-release tablet of claim24 wherein said lubricant is present at about 3% by weight of the coredry weight.
 26. The modified-release tablet of claim 25 wherein saidlubricant is selected from the group consisting of glyceryl behenate,stearic acid, hydrogenated vegetable oils and any combination thereof.27. The modified-release tablet of claim 26 wherein said lubricant isglyceryl behenate.
 28. The modified-release tablet of any one of claims1-27 wherein said control-releasing coat consists essentially of awater-insoluble water-permeable film-forming polymer, a plasticizer anda water-soluble polymer.
 29. The modified-release tablet of claim 28wherein said water-insoluble water-permeable film forming polymer ispresent at about 35% to about 60% by weight of said control-releasingcoat dry weight.
 30. The modified-release tablet of claim 29 whereinsaid water-insoluble water-permeable film forming polymer is present atabout 50% by weight of said control-releasing coat dry weight.
 31. Themodified-release tablet of claim 30 wherein said water-insolublewater-permeable film forming polymer is present at about 45% by weightof the tablet dry weight.
 32. The modified-release tablet of claim 31wherein said water-insoluble water-permeable film forming polymer isselected from the group consisting of a cellulose ether, a celluloseester, polyvinyl alcohol and any combination thereof.
 33. Themodified-release tablet of claim 32 wherein said water-insolublewater-permeable film forming polymer is a cellulose ether.
 34. Themodified-release tablet of claim 33 wherein said cellulose ether isselected from the group consisting of ethyl cellulose grade PR100, ethylcellulose grade PR20 and any combination thereof.
 35. Themodified-release tablet of claim 34 wherein said cellulose ether isethyl cellulose grade PR100.
 36. The modified-release tablet of any oneof claims 28-35 wherein said plasticizer is present from about 6% toabout 30% by weight of said control-releasing coat dry weight.
 37. Themodified-release tablet of claim 36 wherein said plasticizer is presentat about 12% by weight of said control releasing coat dry-weight. 38.The modified-release tablet of claim 37 wherein said plasticizer isselected from the group consisting of polyols, organic esters,oils/glycerides and any combination thereof.
 39. The modified-releasetablet of claim 38 wherein said plasticizer is a polyol.
 40. Themodified-release tablet of claim 39 wherein said polyol is polyethyleneglycol
 1450. 41. The modified-release tablet of any one of claims 28-40wherein said water-soluble polymer is present from about 25% to about50% by weight of said control-releasing coat dry weight.
 42. Themodified-release tablet of claim 41 wherein said water-soluble polymeris present at about 43% by weight of said control-releasing coat dryweight.
 43. The modified-release tablet of claim 42 wherein saidwater-soluble polymer is selected from the group consisting ofpolyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose and any combination thereof.
 44. The modified-release tabletof claim 43 wherein said water-soluble polymer is polyvinylpyrrolidone.45. The modified-release tablet of any one of claims 28-44 wherein theratio of the water-insoluble water permeable film formingpolymer:plasticizer:water-soluble polymer is from about 3:1:4 to about5:1:3.
 46. The modified-release tablet of claim 45 wherein the ratio ofthe water-insoluble water permeable film formingpolymer:plasticizer:water-soluble polymer is about 4:1:3.
 47. Themodified-release tablet of any one of claims 28-44 wherein the ratio ofthe water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer is from about 7:2:6 to about19:5:18.
 48. The modified-release tablet of claim 47 wherein the ratioof the water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer is about 13:4:12.
 49. Themodified-release tablet of claim 28 wherein the weight gained afterapplication of the control-releasing coat is from about 3% to about 30%of the weight of the dry core weight.
 50. The modified-release tablet ofclaim 49 wherein the weight gained after application of thecontrol-releasing coat is from about 13% to about 16% of the weight ofthe dry core weight.
 51. The modified-release tablet of claim 50 whereinthe weight gained after application of the control-releasing coat isfrom about 8% to about 10% of the weight of the dry core weight.
 52. Themodified-release tablet of claim 50 wherein the weight gained afterapplication of the control-releasing coat is about 15% of the weight ofthe dry core weight.
 53. The modified-release tablet of claim 51 whereinthe weight gained after application of the control-releasing coat isabout 9% of the weight of the dry core weight.
 54. The modified-releasetablet of claim 1 wherein said moisture barrier comprises an entericpolymer, a plasticizer and a permeation enhancer.
 55. Themodified-release tablet of claim 54 wherein said enteric polymer ispresent from about 30% to about 90% by weight of the moisture barrierdry weight.
 56. The modified-release tablet of claim 55 wherein saidenteric polymer is present at about 66% by weight of the moisturebarrier dry weight.
 57. The modified-release tablet of claim 56 whereinsaid enteric polymer is methacrylic acid copolymer type C.
 58. Themodified-release tablet of claim 57 wherein the polymer is Eudragit® L30D-55.
 59. The modified-release tablet of claim 54 wherein saidplasticizer is present from about 1% to about 30% by weight of themoisture barrier dry weight.
 60. The modified-release tablet of claim 59wherein said plasticizer is present at about 10% by weight of themoisture barrier dry weight.
 61. The modified-release tablet of claim 60wherein said plasticizer is selected from the group consisting ofpolyols, organic esters, oils/glycerides and any combination thereof.62. The modified-release tablet of claim 61 wherein said plasticizer isa combination of an organic ester and polyol.
 63. The modified-releasetablet of claim 62 wherein said plasticizer combination is in aproportion of about 1 part organic ester to about 2 parts polyol. 64.The modified-release tablet of claim 63 wherein said organic ester istriethyl ester and said polyol is polyethylene glycol
 1450. 65. Themodified-release tablet of claim 54 wherein said permeation enhancer ispresent from about 20% to about 40% by weight of the moisture barrierdry weight.
 66. The modified-release tablet of claim 65 wherein saidpermeation enhancer is present at about 25% by weight of the moisturebarrier dry weight.
 67. The modified-release tablet of claim 66 whereinsaid permeation enhancer is selected from the group consisting ofsilicon dioxide, colloidal silicon, lactose, hydrophilic polymers,sodium chloride, aluminum oxide, colloidal aluminum oxide, silica,microcrystalline cellulose and any combination thereof.
 68. Themodified-release tablet of claim 67 wherein said permeation enhancer issilicon dioxide.
 69. The modified-release tablet of any one of claims54-68 wherein said enteric polymer, plasticizer and permeation enhanceris present in a ratio of about 13:2:5.
 70. The modified-release tabletof claim 54 wherein the weight gained after application of the moisturebarrier is no more than about 6% by weight of the tablet dry weight. 71.The modified-release tablet of claim 70 wherein the weight gained afterapplication of the moisture barrier is no more than about 2.5% by weightof the tablet dry weight.
 72. A modified-release tablet comprising: (i)a core comprising an effective amount of a pharmaceutically acceptablesalt of bupropion, and conventional excipients; (ii) a control-releasingcoat surrounding said core, said control-releasing coat comprising awater-insoluble, water-permeable film-forming polymer, a plasticizer anda water-soluble polymer; and (iii) a moisture barrier surrounding saidcontrol-releasing coat, wherein said moisture barrier does not functionas an enteric coating as defined by a USP test which requires for anenteric layer-coated tablet, when placed in 0.1N HCl for one hour, thatthe total amount of the drug released from the core does not exceed 10%and not less than 75% of the drug is released at 45 minutes in pH 6.8buffer, wherein the modified-release tablet is bioequivalent andexhibits a dissolution profile such that after about 2 hours no morethan about 20% of the bupropion content is released, after about 4 hoursabout 15% to about 45% of the bupropion content is released, after about8 hours about 40% to about 90% of the bupropion content is released andafter about 16 hours no less than about 80% of the bupropion content isreleased.
 73. The modified-release tablet of claim 72 whereinapplication of the moisture barrier to the control-releasing coatedtablet results in a total weight gain of no more than about 6% relativeto the dry tablet weight.
 74. The modified-release tablet of claim 72wherein application of the moisture barrier to the control-releasingcoated tablet results in a total weight gain of no more than about 2.5%relative to the dry tablet weight.
 75. The modified-release tablet ofclaim 72 wherein said moisture barrier is comprised of an entericpolymer, a plasticizer and a permeation enhancer.
 76. Themodified-release tablet of claim 75 wherein the enteric polymer is anacrylic polymer.
 77. The modified-release tablet of claim 76 whereinsaid acrylic polymer is a methacrylic acid copolymer type C.
 78. Themodified-release tablet of claim 77 wherein said polymer is Eudragit®L30 D-55.
 79. The modified-release tablet of claim 75, which comprisesabout 150 mg of said pharmaceutically acceptable salt of bupropion, andthe amount of said enteric polymer ranges from 1% to 3% of the drytablet weight and comprises 55% to 70% of the moisture barrier dryweight.
 80. The modified-release tablet of claim 75, which comprisesabout 300 mg of said pharmaceutically acceptable salt of bupropion, andthe amount of said enteric polymer ranges from 1.5% to 3.0% of the drytablet weight and comprises from 30% to 90% of the moisture barrier dryweight.
 81. The modified-release tablet of claim 80 wherein said entericpolymer is a methacrylic acid copolymer type C.
 82. The modified-releasetablet of claim 80 wherein said enteric polymer is a methacrylic acidcopolymer type C.
 83. The modified-release tablet of claim 81 whereinthe polymer is Eudragit L 30 D-55.
 84. The modified-release tablet ofclaim 82 wherein the polymer is Eudragit L 30 D-55.
 85. Themodified-release tablet of claim 72 wherein the moisture barriercomprises an enteric polymer, a plasticizer, and a permeation enhancer,wherein said enteric polymer is present at about 66% of the moisturebarrier dry weight, said plasticizer is present at about 10% of themoisture barrier dry weight and said permeation enhancer is present atabout 25% of the moisture barrier dry weight, and wherein the weightgained after application of the moisture barrier is no more than about2.5% by weight of the tablet dry weight.
 86. The modified-release tabletof claim 85 wherein said tablet exhibits a dissolution profile such thatafter about 2 hours about 2% to about 18% of the bupropion content isreleased, after about 4 hours about 21% to about 37% of the bupropioncontent is released, after about 8 hours about 60% to about 85% of thebupropion content is released and after about 16 hours no less thanabout 93% of the bupropion content is released.
 87. The modified-releasetablet of claim 86 wherein said tablet exhibits a dissolution profilesuch that after about 2 hours about 4% to about 8% of the bupropioncontent is released, after about 4 hours about 28% to about 34% of thebupropion content is released, after about 8 hours about 68% to about74% of the bupropion content is released and after about 16 hours noless than about 96% of the bupropion content is released.
 88. Themodified-release tablet of claim 87 wherein said tablet exhibits adissolution profile such that after about 2 hours about 5% of thebupropion content is released, after about 4 hours about 32% of thebupropion content is released, after about 8 hours about 74% of thebupropion content is released and after about 16 hours no less thanabout 99% of the bupropion content is released.
 89. The modified-releasetablet of claim 72 wherein said pharmaceutically acceptable salt ofbupropion is bupropion hydrochloride.
 90. The modified-release tablet ofclaim 89 wherein said a pharmaceutically acceptable salt of bupropion ispresent at least at about 94% by weight of the core dry weight.
 91. Themodified-release tablet of claim 72 wherein said conventional excipientsfurther comprise a binder and a lubricant.
 92. The modified-releasetablet of claim 91 wherein said binder is present from about 1% to about6% by weight of the core dry weight.
 93. The modified-release tablet ofclaim 92 wherein said binder is present at about 3% by weight of thecore dry weight.
 94. The modified-release tablet of claim 93 whereinsaid binder is selected from the group consisting of modified starch,gelatin, polyvinylpyrrolidone, cellulose derivatives, polyvinyl alcoholand any combination thereof.
 95. The modified-release tablet of claim 94wherein said binder is polyvinyl alcohol.
 96. The modified-releasetablet of any one of claims 91-95 wherein said lubricant is present fromabout 1% to about 6% by weight of the core dry weight.
 97. Themodified-release tablet of claim 96 wherein said lubricant is present atabout 3% by weight of the core dry weight.
 98. The modified-releasetablet of claim 97 wherein said lubricant is selected from the groupconsisting of glyceryl behenate, stearic acid, hydrogenated vegetableoils and any combination thereof.
 99. The modified-release tablet ofclaim 98 wherein said lubricant is glyceryl behenate.
 100. Themodified-release tablet of claim 72 wherein said water-insolublewater-permeable film forming polymer is present at about 35% to about60% by weight of said control-releasing coat dry weight.
 101. Themodified-release tablet of claim 100 wherein said water-insolublewater-permeable film forming polymer is present at about 50% by weightof said control-releasing coat dry weight.
 102. The modified-releasetablet of claim 100 wherein said water-insoluble water-permeable filmforming polymer is present at about 45% by weight of saidcontrol-releasing coat dry weight.
 103. The modified-release tablet ofany one of claims 100-102 wherein said water-insoluble water-permeablefilm forming polymer is selected from the group consisting of acellulose ether, a cellulose ester, polyvinyl alcohol and anycombination thereof.
 104. The modified-release tablet of claim 103wherein said water-insoluble water-permeable film forming polymer is acellulose ether.
 105. The modified-release tablet of claim 104 whereinsaid cellulose ether is selected from the group consisting of ethylcellulose grade PR100, ethyl cellulose grade PR20 and any combinationthereof.
 106. The modified-release tablet of claim 105 wherein saidcellulose ether is ethyl cellulose grade PR100.
 107. Themodified-release tablet of claim 72 wherein said plasticizer in saidcontrol-releasing coat is present from about 6% to about 30% by weightof said control-releasing coat dry weight.
 108. The modified-releasetablet of claim 107 wherein said plasticizer is said control-releasingcoat is present at about 12% by weight of said control-releasing coatdry weight.
 109. The modified-release tablet of claim 108 wherein saidplasticizer is selected from the group consisting of polyols, organicesters, oils/glycerides and any combination thereof.
 110. Themodified-release tablet of claim 109 wherein said plasticizer is apolyol.
 111. The modified-release tablet of claim 110 wherein saidpolyol is polyethylene glycol
 1450. 112. The modified-release tablet ofclaim 72 wherein said water-soluble polymer is present from about 25% toabout 50% by weight of said control-releasing coat dry weight.
 113. Themodified-release tablet of claim 112 wherein said water-soluble polymeris present at about 43% by weight of said control-releasing coat dryweight.
 114. The modified-release tablet of claim 113 wherein saidwater-soluble polymer is selected from the group consisting ofpolyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, and any combination thereof.
 115. The modified-release tabletof claim 114 wherein said water-soluble polymer is polyvinylpyrrolidone.116. The modified-release tablet of claim 72 wherein the weight gainedafter application of the control-releasing coat is from about 3% toabout 30% of the weight of the dry core weight.
 117. Themodified-release tablet of claim 116 wherein the weight gained afterapplication of the control-releasing coat is from about 13% to about 16%by weight of the dry core weight.
 118. The modified-release tablet ofclaim 117 wherein the weight gained after application of thecontrol-releasing coat is from about 8% to about 10% by weight of thedry core weight.
 119. The modified-release tablet of claim 117 whereinthe weight gained after application of the control-releasing coat is atabout 15% by weight of the dry core weight.
 120. The modified-releasetablet of claim 118 wherein the weight gained after application of thecontrol-releasing coat is at about 9% by weight of the dry core weight.121. The modified-release tablet of claim 71 wherein said entericpolymer is methacrylic acid copolymer C.
 122. The modified-releasetablet of claim 121 wherein the polymer is Eudragit® L30 D-55.
 123. Themodified-release tablet of claim 75 wherein said plasticizer in saidmoisture barrier is selected from the group consisting of polyols,organic esters, oils/glycerides and any combination thereof.
 124. Themodified-release tablet of claim 123 wherein said plasticizer is acombination of an organic ester and polyol.
 125. The modified-releasetablet of claim 124 wherein said plasticizer combination is in aproportion of about 1 part organic ester to about 2 parts polyol. 126.The modified-release tablet of claim 125 wherein said organic ester istriethyl ester and said polyol is polyethylene glycol
 1450. 127. Themodified-release tablet of claim 75 wherein said permeation enhancer insaid moisture barrier is selected from the group consisting of silicondioxide, colloidal silicon, lactose, hydrophilic polymers, sodiumchloride, aluminum oxide, colloidal aluminum oxide, silica,microcrystalline cellulose and any combination thereof.
 128. Themodified-release tablet of claim 127 wherein said permeation enhancer issilicon dioxide.
 129. A modified-release tablet comprising: (i) a corecomprising an effective amount of bupropion hydrochloride, polyvinylalcohol, glyceryl behenate, wherein said bupropion hydrochloride ispresent at least at about 94% by weight of the core dry weight, saidpolyvinyl alcohol is present at about 3% by weight of the core dryweight, and said glyceryl behenate is present at about 3% by weight ofeach core dry weight; (ii) a control-releasing coat surrounding saidcore, said control-releasing coat comprising ethyl cellulose grade PR100, polyethylene glycol 1450, and polyvinylpyrrolidone, wherein saidethyl cellulose grade PR 100 is present from about 45% to about 50% byweight of the control-releasing coating dry weight, said polyethyleneglycol 1450 is present at about 12% by weight of the control-releasingcoating dry weight, and said polyvinylpyrrolidone is present from about25% to about 50% of the control-releasing coat dry weight, wherein theamount of said control-releasing coat applied is from about 9% to about15% by weight of the dry tablet core; and (iii) a moisture barriersurrounding said control-releasing coat, said moisture barriercomprising methacrylic acid copolymer, polyethylene glycol 1450,triethyl citrate and silicon dioxide, wherein said methacrylic acidcopolymer is present at about 66% by weight of said moisture barrier dryweight, said polyethylene glycol 1450 and triethyl citrate is present atabout 10% by weight of said moisture barrier dry weight in a proportionof 1 part triethyl citrate to 2 parts polyethylene glycol 1450, and saidsilicon dioxide is present at about 25% by weight of said moisturebarrier dry weight, wherein the amount of the said moisture barrierapplied is no more than about 2.5% of the tablet dry weight; whereinsaid modified-release tablet is bioequivalent and exhibits a dissolutionprofile such that after about 2 hours about 5% of the bupropionhydrochloride content is released, after about 4 hours, about 32% of thebupropion hydrochloride content is released, after about 8 hours, about74% of the bupropion hydrochloride content is released and after about16 hours no less than about 99% of the bupropion hydrochloride contentis released.
 130. A modified-release tablet comprising: (i) a corecomprising an effective amount of bupropion hydrochloride andconventional excipients; (ii) a control-releasing coat surrounding saidcore, said control-releasing coat comprising a water-insoluble,water-permeable film-forming polymer, a plasticizer and a water-solublepolymer; and (iii) a moisture barrier surrounding said control-releasingcoat, said moisture barrier comprising, methacrylic acid copolymer,polyethylene glycol 1450, triethyl citrate and silicon dioxide, whereinsaid methacrylic acid copolymer is present at about 66% by weight ofsaid moisture barrier dry weight, said polyethylene glycol 1450 andtriethyl citrate is present at about 10% by weight of said moisturebarrier dry weight in a proportion of about 1 part triethyl citrate toabout 2 parts polyethylene glycol 1450 and said silicon dioxide ispresent at about 25% by weight of said moisture barrier dry weight,wherein the amount of the said moisture barrier applied is no more thanabout 2.5% of the tablet dry weight, wherein said modified-releasetablet is bioequivalent and wherein said modified-release tablet whenadministered to a patient in need of such administration in the fastedstate provides a C_(max) of bupropion in the blood plasma at betweenabout 3 hours and about 8 hours (T_(max)) after administration of themodified-release tablet.
 131. A modified-release tablet comprising: (i)a core comprising an effective amount of bupropion hydrochloride andconventional excipients; (ii) a control-releasing coat surrounding saidcore, said control-releasing coat comprising a water-insolublewater-permeable film-forming polymer, a plasticizer and a water-solublepolymer; and (iii) a moisture barrier surrounding said control-releasingcoat, said moisture barrier comprising, methacrylic acid copolymer,polyethylene glycol 1450, triethyl citrate and silicon dioxide, whereinsaid methacrylic acid copolymer is present at about 66% by weight ofsaid moisture barrier dry weight, said polyethylene glycol 1450 andtriethyl citrate is present at about 10% by weight of said moisturebarrier dry weight in a proportion of about 1 part triethyl citrate toabout 2 parts polyethylene glycol 1450 and said silicon dioxide ispresent at about 25% by weight of said moisture barrier dry weightwherein the amount of the said moisture barrier applied is no more thanabout 2.5% of the tablet dry weight, wherein said modified-releasetablet is bioequivalent and wherein said modified-release tablet whenadministered to a patient in need of such administration in the fastedstate provides a C_(max) of bupropion in the blood plasma at about 5hours (T_(max)) after administration of the modified-release tablet.132. A modified-release tablet comprising: (i) a core comprising aneffective amount of bupropion hydrochloride and conventional excipients;(ii) a control-releasing coat surrounding said core, saidcontrol-releasing coat comprising a water-insoluble water-permeablefilm-forming polymer, a plasticizer and a water-soluble polymer; and(iii) a moisture barrier surrounding said control-releasing coat, saidmoisture barrier comprising, methacrylic acid copolymer, polyethyleneglycol 1450, triethyl citrate and silicon dioxide, wherein saidmethacrylic acid copolymer is present at about 66% by weight of saidmoisture barrier dry weight, said polyethylene glycol 1450 and triethylcitrate is present at about 10% by weight of said moisture barrier dryweight in a proportion of about 1 part triethyl citrate to about 2 partspolyethylene glycol 1450 and said silicon dioxide is present at about25% by weight of said moisture barrier dry weight wherein the amount ofthe said moisture barrier applied is no more than about 2.5% of thetablet dry weight, wherein said modified-release tablet is bioequivalentand wherein said modified-release tablet when administered to a patientin need of such administration in the fasted state provides a C_(max) ofbupropion ranging from about 60 ng/ml to about 280 ng/ml in the bloodplasma at about 5 hours (T_(max)) after administration of a once daily300 mg dose of said modified-release bupropion hydrochloride tablet or a2×150 mg dose once daily of said modified-release bupropionhydrochloride tablet.
 133. A modified-release tablet comprising: (i) acore comprising an effective amount of bupropion hydrochloride andconventional excipients; (ii) a control-releasing coat surrounding saidcore, said control-releasing coat comprising a water-insolublewater-permeable film-forming polymer, a plasticizer and a water-solublepolymer; and (iii) a moisture barrier surrounding said control-releasingcoat, said moisture barrier comprising, methacrylic acid copolymer,polyethylene glycol 1450, triethyl citrate and silicon dioxide, whereinsaid methacrylic acid copolymer is present at about 66% by weight ofsaid moisture barrier dry weight, said polyethylene glycol 1450 andtriethyl citrate is present at about 10% by weight of said moisturebarrier dry weight in a proportion of about 1 part triethyl citrate toabout 2 parts polyethylene glycol 1450 and said silicon dioxide ispresent at about 25% by weight of said moisture barrier dry weightwherein the amount of the said moisture barrier applied is no more thanabout 2.5% of the tablet dry weight, wherein said modified-releasetablet is bioequivalent and wherein said modified-release tablet whenadministered to a patient in need of such administration in the fastedstate exhibits a blood plasma concentration profile for bupropion asshown in FIG. 3A after administration of a once daily 300 mg dose ofsaid modified-release bupropion hydrochloride tablet or a 2×150 mg doseonce daily of said modified-release bupropion hydrochloride tablet. 134.A modified-release tablet comprising: (i) a core comprising an effectiveamount of bupropion hydrochloride and conventional excipients; (ii) acontrol-releasing coat surrounding said core, said control-releasingcoat comprising a water-insoluble, water-permeable film-forming polymer,a plasticizer and a water-soluble polymer, and (iii) a moisture barriersurrounding said control-releasing coat, said moisture barriercomprising, methacrylic acid copolymer, polyethylene glycol 1450,triethyl citrate and silicon dioxide, wherein said methacrylic acidcopolymer is present at about 66% by weight of said moisture barrier dryweight, said polyethylene glycol 1450 and triethyl citrate is present atabout 10% by weight of said moisture barrier dry weight in a proportionof about 1 part triethyl citrate to about 2 parts polyethylene glycol1450 and said silicon dioxide is present at about 25% by weight of saidmoisture barrier dry weight wherein the amount of the said moisturebarrier applied is no more than about 2.5% of the tablet dry weight,wherein said modified-release tablet is bioequivalent and wherein saidmodified-release tablet when administered to a patient in need of suchadministration in the fasted state exhibits an AUC_((0-t)) for bupropionfrom about 800 ng·hr/ml to about 2850 ng·hr/ml after administration of aonce daily 300 mg dose of said modified-release bupropion hydrochloridetablet or a 2×150 mg dose once daily of said modified-release bupropionhydrochloride tablet.
 135. A modified-release tablet comprising: (i) acore comprising an effective amount of bupropion hydrochloride andconventional excipients; (ii) a control-releasing coat surrounding saidcore, said control-releasing coat comprising a water-insolublewater-permeable film-forming polymer, a plasticizer and a water-solublepolymer; and (iii) a moisture barrier surrounding said control-releasingcoat, said moisture barrier comprising, methacrylic acid copolymer,polyethylene glycol 1450, triethyl citrate and silicon dioxide, whereinsaid methacrylic acid copolymer is present at about 66% by weight ofsaid moisture barrier dry weight, said polyethylene glycol 1450 andtriethyl citrate is present at about 10% by weight of said moisturebarrier dry weight in a proportion of about 1 part triethyl citrate toabout 2 parts polyethylene glycol 1450 and said silicon dioxide ispresent at about 25% by weight of said moisture barrier dry weight,wherein the amount of the said moisture barrier applied is no more thanabout 2.5% of the tablet dry weight, wherein said modified-releasetablet is bioequivalent and wherein said modified-release tablet whenadministered to a patient in need of such administration in the fastedstate exhibits an AUC_((0-inf)) for bupropion from about 840 ng·hr/ml toabout 3000 ng·hr/ml after administration of a once daily 300 mg dose ofsaid modified-release bupropion hydrochloride tablet or a 2×150 mg doseonce daily of said modified-release bupropion hydrochloride tablet. 136.A modified-release tablet comprising: (i) a core comprising an effectiveamount of bupropion hydrochloride and conventional excipients; (ii) acontrol-releasing coat surrounding said core, said control-releasingcoat comprising a water-insoluble water-permeable film-forming polymer,a plasticizer and a water-soluble polymer, and (iii) a moisture barriersurrounding said control-releasing coat, said moisture barriercomprising, methacrylic acid copolymer, polyethylene glycol 1450,triethyl citrate and silicon dioxide, wherein said methacrylic acidcopolymer is present at about 66% by weight of said moisture barrier dryweight, said polyethylene glycol 1450 and triethyl citrate is present atabout 10% by weight of said moisture barrier dry weight in a proportionof about 1 part triethyl citrate to about 2 parts polyethylene glycol1450 and said silicon dioxide is present at about 25% by weight of saidmoisture barrier dry weight, wherein the amount of the said moisturebarrier applied is no more than about 2.5% of the tablet dry weight,wherein said modified-release tablet when administered as a 2×150 mgdose once daily or a 300 mg dose once daily to a patient in need of suchadministration in the fasted state is bioequivalent toZyban®/Wellbutrin®SR.
 137. A modified-release tablet comprising: (i) acore comprising an effective amount of bupropion hydrochloride andconventional excipients; (ii) a control-releasing coat surrounding saidcore, said control-releasing coat comprising a water-insolublewater-permeable film-forming polymer, a plasticizer and a water-solublepolymer, and (iii) a moisture barrier surrounding said control-releasingcoat, said moisture barrier comprising, methacrylic acid copolymer,polyethylene glycol 1450, triethyl citrate and silicon dioxide, whereinsaid methacrylic acid copolymer is present at about 66% by weight ofsaid moisture barrier dry weight, said polyethylene glycol 1450 andtriethyl citrate is present at about 10% by weight of said moisturebarrier dry weight in a proportion of about 1 part triethyl citrate toabout 2 parts polyethylene glycol 1450 and said silicon dioxide ispresent at about 25% by weight of said moisture barrier dry weight,wherein the amount of the said moisture barrier applied is no more thanabout 2.5% of the tablet dry weight; wherein said modified-releasetablet administered as a 2×150 mg dose once daily or a 300 mg doseadministered once daily to a patient in need of such administration doesnot exhibit a food effect.
 138. A modified-release tablet comprising:(i) a core comprising an effective amount of a pharmaceuticallyacceptable salt of bupropion hydrochloride and conventional excipients;(ii) a control-releasing coat surrounding said core, saidcontrol-releasing coat comprising a water-insoluble water-permeablefilm-forming polymer, a plasticizer and a water-soluble polymer, and(iii) a moisture barrier surrounding said control-releasing coat, saidmoisture barrier comprising, methacrylic acid copolymer, polyethyleneglycol 1450, triethyl citrate and silicon dioxide, wherein saidmethacrylic acid copolymer is present at about 66% by weight of saidmoisture barrier dry weight, said polyethylene glycol 1450 and triethylcitrate is present at about 10% by weight of said moisture barrier dryweight in a proportion of about 1 part triethyl citrate to about 2 partspolyethylene glycol 1450 and said silicon dioxide is present at about25% by weight of said moisture barrier dry weight, wherein the amount ofthe said moisture barrier applied is no more than about 2.5% of thetablet dry weight; wherein said modified-release tablet is bioequivalentand wherein a single dose of said modified-release tablet whenadministered to a patient in need of such administration in the fastedor fed state exhibits mean plasma concentration-time curves as shown inFIG. 4A.
 139. A modified-release tablet comprising: (i) a corecomprising an effective amount of bupropion hydrochloride andconventional excipients; (ii) a control-releasing coat surrounding saidcore, said control-releasing coat comprising a water-insolublewater-permeable film-forming polymer, a plasticizer and a water-solublepolymer, and (iii) a moisture barrier surrounding said control-releasingcoat, said moisture barrier comprising, methacrylic acid copolymer,polyethylene glycol 1450, triethyl citrate and silicon dioxide, whereinsaid methacrylic acid copolymer is present at about 66% by weight ofsaid moisture barrier dry weight, said polyethylene glycol 1450 andtriethyl citrate is present at about 10% by weight of said moisturebarrier dry weight in a proportion of about 1 part triethyl citrate toabout 2 parts polyethylene glycol 1450 and said silicon dioxide ispresent at about 25% by weight of said moisture barrier dry weight,wherein the amount of the said moisture barrier applied is no more thanabout 2.5% of the tablet dry weight, wherein said modified-releasetablet when administered as a 300 mg dose once daily to a patient inneed of such administration in the fasted state is bioequivalent toWellbutrin® tablets administered 1×300 mg (t.i.d) at steady state. 140.A modified-release tablet comprising: (i) a core comprising an effectiveamount of bupropion hydrochloride and conventional excipients; (ii) acontrol-releasing coat surrounding said core, said control-releasingcoat comprising a water-insoluble water-permeable film-forming polymer,a plasticizer and a water-soluble polymer, and (iii) a moisture barriersurrounding said control-releasing coat, said moisture barriercomprising, methacrylic acid copolymer, polyethylene glycol 1450,triethyl citrate and silicon dioxide, wherein said methacrylic acidcopolymer is present at about 66% by weight of said moisture barrier dryweight, said polyethylene glycol 1450 and triethyl citrate is present atabout 10% by weight of said moisture barrier dry weight in a proportionof about 1 part triethyl citrate to about 2 parts polyethylene glycol1450 and said silicon dioxide is present at about 25% by weight of saidmoisture barrier dry weight, wherein the amount of the said moisturebarrier applied is no more than about 2.5% of the tablet dry weight,wherein said modified-release tablet when administered as a 300 mg doseonce daily to a patient in need of such administration in the fastedstate is bioequivalent to Zyban® administered 1×150 mg twice daily(b.i.d.) at steady state.
 141. A modified-release tablet comprising: (i)a core comprising an effective amount of bupropion hydrochloride andconventional excipients; (ii) a control-releasing coat surrounding saidcore, said control-releasing coat comprising a water-insolublewater-permeable film-forming polymer, a plasticizer and a water-solublepolymer, and (iii) a moisture barrier surrounding said control-releasingcoat, said moisture barrier comprising, methacrylic acid copolymer,polyethylene glycol 1450, triethyl citrate and silicon dioxide, whereinsaid methacrylic acid copolymer is present at about 66% by weight ofsaid moisture barrier dry weight, said polyethylene glycol 1450 andtriethyl citrate is present at about 10% by weight of said moisturebarrier dry weight in a proportion of about 1 part triethyl citrate toabout 2 parts polyethylene glycol 1450 and said silicon dioxide ispresent at about 25% by weight of said moisture barrier dry weight,wherein the amount of the said moisture barrier applied is no more thanabout 2.5% of the tablet dry weight, wherein the moisture content is nomore than about 0.4% in said tablet when stored at 40° C.±2° C./75%RH±5% RH in an open dish after about 10 days.
 142. A modified-releasetablet comprising: (i) a core comprising an effective amount ofbupropion hydrochloride and conventional excipients; (ii) acontrol-releasing coat surrounding said core, said control-releasingcoat comprising a water-insoluble water-permeable film-forming polymer,a plasticizer and a water-soluble polymer, and (iii) a moisture barriersurrounding said control-releasing coat, said moisture barriercomprising, methacrylic acid copolymer, polyethylene glycol 1450,triethyl citrate and silicon dioxide, wherein said methacrylic acidcopolymer is present at about 66% by weight of said moisture barrier dryweight, said polyethylene glycol 1450 and triethyl citrate is present atabout 10% by weight of said moisture barrier dry weight in a proportionof about 1 part triethyl citrate to about 2 parts polyethylene glycol1450 and said silicon dioxide is present at about 25% by weight of saidmoisture barrier dry weight, wherein the amount of the said moisturebarrier applied is no more than about 2.5% of the tablet dry weight,wherein said tablet contains at least about 95% undegraded bupropionhydrochloride after storage for 12 months at about 25° C.±2° C./60%RH±5% RH.
 143. The tablet of claim 142 wherein said tablet contains atleast about 97% undegraded bupropion hydrochloride after storage for 12months at about 25° C.±2° C./60% RH±5% RH.
 144. The tablet of claim 142wherein said tablet contains at least about 98% undegraded bupropionhydrochloride after storage for 12 months at about 25° C.±2° C./60%RH±5% RH.
 145. The tablet of claim 142 wherein said tablet contains atleast about 99% undegraded bupropion hydrochloride after storage for 12months at about 25° C.±2° C./60% RH±5% RH.
 146. A modified-releasetablet comprising: (i) a core comprising an effective amount ofbupropion hydrochloride and conventional excipients; (ii) acontrol-releasing coat surrounding said core, said control-releasingcoat comprising a water-insoluble water-permeable film-forming polymer,a plasticizer and a water-soluble polymer, and (iii) a moisture barriersurrounding said control-releasing coat, said moisture barriercomprising, methacrylic acid copolymer, polyethylene glycol 1450,triethyl citrate and silicon dioxide, wherein said methacrylic acidcopolymer is present at about 66% by weight of said moisture barrier dryweight, said polyethylene glycol 1450 and triethyl citrate is present atabout 10% by weight of said moisture barrier dry weight in a proportionof about 1 part triethyl citrate to about 2 parts polyethylene glycol1450 and said silicon dioxide is present at about 25% by weight of saidmoisture barrier dry weight, wherein the amount of the said moisturebarrier applied is no more than about 2.5% of the tablet dry weight,wherein the moisture content is no more than about 1% in said tabletwhen stored at 40° C.±2° C./75% RH±5% RH after storage for about 6months.
 147. A modified-release tablet comprising: (i) a core comprisingan effective amount of bupropion hydrochloride and conventionalexcipients; (ii) a control-releasing coat surrounding said core, saidcontrol-releasing coat comprising a water-insoluble water-permeablefilm-forming polymer, a plasticizer and a water-soluble polymer, and(iii) a moisture barrier surrounding said control-releasing coat, saidmoisture barrier comprising, methacrylic acid copolymer, polyethyleneglycol 1450, triethyl citrate and silicon dioxide, wherein saidmethacrylic acid copolymer is present at about 66% by weight of saidmoisture barrier dry weight, said polyethylene glycol 1450 and triethylcitrate is present at about 10% by weight of said moisture barrier dryweight in a proportion of about 1 part triethyl citrate to about 2 partspolyethylene glycol 1450 and said silicon dioxide is present at about25% by weight of said moisture barrier dry weight, wherein the amount ofthe said moisture barrier applied is no more than about 2.5% of thetablet dry weight, wherein said tablet contains at least about 95%undegraded bupropion hydrochloride after storage for 18 months at about25° C.±2° C./60% RH±5% RH.
 148. The tablet of claim 147 wherein saidtablet contains at least about 97% undegraded bupropion hydrochlorideafter storage for 18 months at about 25° C.±2° C./60% RH±5% RH.
 149. Thetablet of claim 147 wherein said tablet contains at least about 98%undegraded bupropion hydrochloride after storage for 18 months at about25° C.±2° C./60% RH±5% RH.
 150. The tablet of claim 147 wherein saidtablet contains at least about 99% undegraded bupropion hydrochlorideafter storage for 18 months at about 25° C.±2° C./60% RH±5% RH.
 151. Themodified-release tablet of claims 18, 30, 36, 41, 46, 52, 56, 60, 66,69, 71, 90, 101, 108, 112, 119, or 141-150, wherein said tablet contains150 mg of bupropion hydrochloride.
 152. The modified-release tablet ofclaims 18, 31, 36, 42, 48, 53, 56, 60, 66, 69, 71, 90, 102, 108, 113,120, or 141-150, wherein said tablet contains 300 mg of bupropionhydrochloride.
 153. A modified-release tablet comprising: (i) a corecomprising about 150 mg of bupropion hydrochloride, about 5.3 mgpolyvinyl alcohol, about 4.7 mg glyceryl behenate; (ii) acontrol-releasing coat surrounding said core, said control-releasingcoat comprising about 12 mg ethyl cellulose grade PR 100, about 3 mgpolyethylene glycol 1450, and about 9 mg polyvinylpyrrolidone, whereinabout 24 mg of the control releasing coat is applied onto said core; and(iii) a moisture barrier surrounding said control-releasing coat, saidmoisture barrier comprising about 4.6 mg methacrylic acid copolymer,about 0.46 mg polyethylene glycol 1450, about 0.23 mg triethyl citrateand about 1.72 mg silicon dioxide, wherein about 7 mg of the moisturebarrier is applied onto the control releasing coated cores, and whereinsaid modified-release tablet is bioequivalent and exhibits a dissolutionprofile such that after about 2 hours about 5% of the bupropionhydrochloride content is released, after about 4 hours, about 32% of thebupropion hydrochloride content is released, after about 8 hours, about74% of the bupropion hydrochloride content is released and after about16 hours no less than about 99% of the bupropion hydrochloride contentis released.
 154. A modified-release tablet comprising: (i) a corecomprising about 300 mg of bupropion hydrochloride, about 10.6 mgpolyvinyl alcohol, about 9.4 mg glyceryl behenate; (ii) acontrol-releasing coat surrounding said core, said control-releasingcoat comprising about 13.1 mg ethyl cellulose grade PR 100, about 3.6 mgpolyethylene glycol 1450, and 12.4 mg polyvinylpyrrolidone, whereinabout 29 mg of the control releasing coat is applied onto said core; and(iii) a moisture barrier surrounding said control-releasing coat, saidmoisture barrier comprising about 6.9 mg methacrylic acid copolymer,about 0.7 mg polyethylene glycol 1450, 0.35 mg triethyl citrate andabout 2.6 mg silicon dioxide, wherein about 10.5 mg of the moisturebarrier is applied onto the control releasing coated cores, and whereinsaid modified-release tablet is bioequivalent and exhibits a dissolutionprofile such that after about 2 hours about 5% of the bupropionhydrochloride content is released, after about 4 hours, about 32% of thebupropion hydrochloride content is released, after about 8 hours, about74% of the bupropion hydrochloride content is released and after about16 hours no less than about 99% of the bupropion hydrochloride contentis released.